JPH0751564B2 - Piperidinylcamphosulfonyloxytocin antagonist - Google Patents

Description

Detailed Description of the Invention

The present invention provides novel compounds, novel compositions, methods for their use and methods for their preparation. Such compounds are generally useful pharmacologically as obstetric and gynecologic therapeutic agents. The above pharmacological activity is useful for treating mammals. More specifically, the compounds of the invention can be used in the treatment of preterm birth, arrest of labor prior to Caesarean birth and treatment of dysmenorrhea. Currently, there is a need for such drugs in the area of obstetrics and gynecologic therapy.

In the field of obstetrics, one of the most important issues is the management of preterm birth. A significant number of pregnant women after the 20th week of gestation experience preterm birth and childbirth, which is a major cause of neonatal morbidity and mortality. Despite major advances in neonatal care, retaining the fetus in the womb is almost always preferred.

Among the currently used labor control (uterine relaxants) agents are β ₂ -adrenergic agents, magnesium sulfate and ethanol. The major β ₂ -adrenergic agonist ritodrine causes some cardiovascular and metabolic side effects in the mother, including tachycardia, increased renin secretion, hyperglycemia (and reactive hypoglycemia in infants). Other β ₂ -adrenergic agents, including terbutaline and albuterol, have similar side effects to ritodrine. Magnesium sulphate may cause cardiac conduction and neuromuscular transmission inhibition, respiratory depression and cardiac arrest at plasma concentrations above the therapeutic range of 4-8 mg / dl, making this drug unsuitable if renal function is impaired. Make something Ethanol is as effective as ritodrine in preventing preterm birth, but does not show a corresponding decrease in the incidence of fetal respiratory asphyxia resulting from administration of ritodrine.

It has been proposed that selective oxytocin antagonists would be ideal birth control agents. Over the past few years, there has been accumulating evidence strongly suggesting that oxytocin is a physiological initiator of labor in several mammalian species, including humans. Oxytocin is believed to exert this effect in part by directly contracting the myometrium and in part by enhancing the synthesis and release of contractile prostaglandins from the endometrium / decidua. In addition, these prostaglandins may be important in the cervical ripening process.
By these mechanisms, the labor (due and early) process is initiated with uterine sensitization to oxytocin, partly as a result of a well-documented increase in the number of oxytocin receptors in this tissue. This "Up-regulation" of the oxytocin receptor and uterine sensitivity is likely due to the tropic effect of increasing plasma levels of estrogen towards the deadline. By blocking both the direct (contractile) and indirect (high prostaglandin synthesis) effects of oxytocin in the uterus,
Selective oxytocin antagonists are probably more effective at treating preterm birth than current methods. In addition, since oxytocin has a major effect on the uterus only on a due date, such compounds are considered to have only minor side effects, if any.

The compounds of the present invention are also useful in treating dysmenorrhea. This condition is characterized by periodic pain associated with menstruation during the ovulation cycle. The pain is probably due to uterine contractions and ischemia mediated by the effects of prostaglandins produced in the secretory endometrium. By blocking both the direct and indirect effects of oxytocin on the uterus, selective oxytocin antagonists are more effective at treating dysmenorrhea than current methods.

The application of the present invention also relates to the termination of labor prior to Caesarean delivery. Certain spiroindanyl piperidines and spiroindenyl piperidines are known (US Pat. Nos. 3,654,287 and 3,666).
No. 764), however, they are reported to be useful as anesthetic agents which is entirely different from the use of the present invention.

Therefore, an animal, preferably a mammal,
It is an object of the present invention to identify substances that more effectively antagonize the function of oxytocin, especially with regard to pathology in humans. It is another object of the present invention to prepare new compounds that selectively inhibit oxytocin. It is yet another object of the invention to develop a method of antagonizing the function of oxytocin with respect to pathological conditions in mammals. It is also an object of the present invention to develop a method of preventing or treating oxytocin-related disorders, especially preterm labor and dysmenorrhea.

It has now been found that the compounds of formula I are oxytocin antagonists and bind to the oxytocin receptor. These compounds are useful for treating and preventing oxytocin-related disorders in animals, preferably mammals, especially humans. These disorders are mainly preterm labor and dysmenorrhea. The compounds also have utility in stopping labor prior to Caesarean delivery.

The compounds of the present invention are compounds of the following general structural formula I:

[Chemical 10] And pharmaceutically acceptable salts thereof:

In the above formula: X is C = O CH ₂ PO ₂ H O PO ₂ H-OY (Y is C _1-10 alkyl) S SO SO ₂

[Chemical 11] Or SO ₂ NH;

M is an integer of 1 to 3; n is an integer of 0 to 2; p is an integer of 0 to 2; q is an integer of 0 to 1; r is an integer of 0 to 5 Is;

R ¹ and R ² are each independently hydrogen halogen hydroxy C _1-10 alkyl C _1-10 alkoxy or trifluoromethyl;

R ³ is hydrogen alkyl halogen hydroxy or oxo; when R ³ is oxo, the 2,3 bond is saturated;

R ⁴ is hydrogen phenyl C _1-10 hydroxyalkyl or C _1-15 alkyl;

R ⁵ and R ⁶ are each independently hydrogen or C _1-10 alkyl;

Further, R ⁵ and R ⁶ are taken together to form an oxo-fused phenyl or an unsubstituted or substituted C _3-6 cycloalkyl (the above substituents are hydroxy C _1-10 alkyl C _1-10 hydroxyalkyl). C _1-10 alkoxy or C _1-10 alkoxyalkoxyalkoxyalkyl);

R ⁷ , R ⁸ and R ⁹ are each independently hydrogen unsubstituted or substituted C _1-10 alkyl (wherein the above substituents are cyano (when C is 2-10) hydroxy carboxy C _1-10 alkoxy C _1-10 alkoxycarbonyl or an unsubstituted or substituted 5-membered heterocycle having one heteroatom (wherein said heteroatom is N; said substituent is oxo amino C _1-10 alkylamino C _1-10 carboxyalkylcarbonylamino C _1-10 dicarboxyalkylamino or C _1-10 dialkoxycarbonylalkylamino) is) C _1-10 dialkyl C _7-10 alkoxy C _1-10 alkoxycarbonyl C _1-10 alkoxycarbonylalkylaminocarbonyl fused phenyl cyano C _2-10 cyanoalkyl phosphates C _1-10 alkyl-substituted phosphonate sulphate C _1-10 Alkyl substituted sulfonate halogen-substituted C _1-10 alkyl-substituted sulfonates

[Chemical 11] (R ¹⁰ is hydrogen C _1-10 alkylsulfonyl C _1-10 alkarylsulfonyl C _1-10 aralkylsulfonyl C _1-10 alkoxyarylsulfonyl aminosulfonyl C _1-10 alkylaminosulfonyl C _1-10 dialkylaminosulfonyl unsubstituted or Substituted C _3-15 cycloalkylalkyl, bicycloalkyl or tricycloalkyl (substituent is oxo) or unsubstituted or substituted C _3-15 cycloalkylalkyl, bicycloalkyl or tricycloalkyl (substituent is oxo, oxime or A sulfonyl substituted with a hydroxy));

R ¹¹ is hydrogen C _1-10 alkyl C _1-10 carboxyalkyl or C _1-10 alkoxycarbonylalkyl)

[Chemical 12] (R ¹¹ is as defined above; R ¹² is hydrogen amino C _1-10 alkylamino

Unsubstituted or substituted C _1-10 alkyl (wherein the above substituents are unsubstituted or substituted C _4-8 cycloalkyl (substituents are hydroxy or carboxy) C _10-15 bi and tricycloalkyl halogen hydroxy carboxy oxo) Oxime C _1-10 alkylthio C _1-10 alkylsulfinyl C _1-10 alkylsulfonyl C _1-10 alkoxycarbonyl Unsubstituted or substituted having 1, 2, 3 or 4 heteroatoms or moieties 4, 5, 6 or 7 members Heterocycle (where the heteroatom or moiety is N, S, SO, SO ₂ or O; the substituents are C _1-10 alkyl C _1-10 aralkyl C _1-10 aralkoxy C _1-10 alkaryl amino C _1-10 Alkylamino oxo oxime Fused phenyl C _1-10 alkoxycarbonyl C _1-10 alkyl carbonate C _1-10 alkylureido C _1-10 alkyl Carbamate or an unsubstituted or substituted 5, 6 or 7 membered heterocycle having 1, 2, 3 or 4 heteroatoms (where the heteroatoms are N, O
Or S; the substituent is oxo or fused phenyl). )

Unsubstituted or substituted phenyl (wherein the above substituents are halogen hydroxy carboxy C _1-10 alkyl C _1-10 carboxyalkyl C _1-10 alkoxy sulphate or 5, 6 or having 1, 2, 3 or 4 heteroatoms 7-membered heterocycle (heteroatom is N, O or S)
Amino aminocarbonyl C _1-10 dialkylaminocarbonyl C _1-10 alkylamino C _1-10 dialkylamino C _1-10 alkyl carbamate C _1-10 alkyl carbonate C _1-10 alkylureido C _1-10 aralkyl carbamate Substituted or substituted aryloxy (substituent is amino,
C _1-10 alkyl or C _1-10 aminoalkyl) C _1-10 aralkyloxy unsubstituted or substituted C _1-10 alkaryloxy (substituent is C _1-10 alkyl carbamate) N, N—C _1-10 alkyl-C _1-10 carboxyalkyl or N, N, N-C _1-10 dialkyl-C _1-10 alkoxycarboxyalkyl) unsubstituted or substituted C _3-8 cycloalkyl (substituent is C
_1-10 alkyl or carboxy) N, N-C _1-10 dialkyl unsubstituted or substituted C _5-15 bicycloalkyl or tricycloalkyl (substituent is carboxy) C _1-10 alkoxy

Unsubstituted or substituted phenyl (wherein the above substituents are amino halogen C _1-10 alkyl C _1-10 alkoxy nitro phenylcarbonyl or unsubstituted or substituted 5, 6 or 1 having 1, 2, 3 or 4 heterocyclic atoms A 7-membered heterocycle (where the heteroatom is O, N or S; the substituent is oxo), an unsubstituted or substituted 4,5, 6, having 1, 2, 3 or 4 heteroatoms or moieties. 7- or 8-membered mono- or bicycloheterocycle (where heteroatoms or moieties are N, O, S,
SO or SO ₂ ; the substituent is oxo hydroxy carboxy amino C _1-10 carboxyalkyl C _1-10 alkyl C _1-10 alkoxy C _1-10 aralkoxy C _1-10 alkaryloxy C _1-10 alkoxycarbonyl C _{1 -10} alkoxycarbonylamino C _1-10 alkoxycarbonylalkyl C _1-10 aralkoxycarbonyl or substituted or unsubstituted aryl (substituent is C _1-5 alkyl, carboxy or halogen). ;

Further, R ⁷ and R ⁸ together are a 5, 6 or 7 membered heterocycle having 2, 3 or 4 heteroatoms (where the heteroatoms are N, O or S)-(CH ₂ ) _r -CO-NH-R ¹³ (R ¹³ is C _1-10 alkyl C _1-10 aminoalkyl C _1-10 alkoxycarbonylalkyl C _1-10 carboxyalkyl or an 8-membered bicycloheterocycle having 1 or 2 heteroatoms ( The heteroatom is N)-(CH ₂ ) _r NH-CO-NH-R ¹⁴ (R ¹⁴ is hydrogen-substituted or unsubstituted C _1-10 alkyl, C _7-15 bi- or tricycloalkyl (above-mentioned. Substituent is carboxy C _1-10 alkoxycarbonyl aminocarbonyl or C _1-10 carboxyalkyl) A substituted or unsubstituted 5, 6 or 7 membered heterocycle having 1 or 2 heteroatoms or moieties (where the heteroatoms or moieties are N, O, S, SO Is SO _2; substituent forms a a a) oxo carboxy amino C _1-10 carboxyalkyl C _1-10 alkyl or C _1-10 alkoxycarbonylamino)].

The term salt included within the term "pharmaceutically acceptable salt" refers to the non-toxic salts of compounds of the present invention which are typically prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following salts: acetic acid, benzenesulfonic acid, benzoic acid, hydrogen carbonate, hydrogen sulfate, hydrogen tartrate, boric acid, bromide, calcium edetate, cansylic acid, carbonic acid, chloride, clavulanic acid. , Citric acid, dihydrochloride, edetic acid, edisylic acid, estolic acid,
Esylic acid, fumaric acid, gluceptic acid, gluconic acid, glutamic acid, glycolylarsanilic acid, hexylresorcinic acid, hydrabamine, hydrobromic acid, hydrochloric acid, hydroxynaphthoic acid, iodide, isethionic acid, lactic acid, lactobionic acid, lauric acid , Malic acid, maleic acid, mandelic acid, mesylic acid, methyl bromide, methyl nitric acid, methyl sulfate, mutic acid, napsyl acid, nitric acid, oleic acid, oxalic acid, pamoic acid (embonic acid), palmitic acid, pantothenic acid, phosphorus Acid salts of nonilic acid, polygalacturonic acid, salicylic acid, stearic acid, basic acetic acid, succinic acid, tannic acid, tartaric acid, theocric acid, tosylic acid, triethiozide, valeric acid.

The term "pharmacologically effective amount" means tissue,
It refers to the amount of a drug or agent that develops a biological or medical response in a system, animal or human, which has been investigated by a researcher or clinician. The term "alkyl" means straight or branched chain alkanes, alkenes and alkyls that may have one or more degrees of unsaturation at any position in the chain.

The term "aryl" means phenyl. The term "cycloalkyl" means an alkane, alkene or alkyne cyclocycle which may have one or more degrees of unsaturation at any position on the ring.

When the terms "alkyl", "aryl" or any of their prefix roots appear in the name of a substituent (eg aralkoxyaryloxy), they are "alkyl" and "aryl." Is intended to be inclusive of the restrictions set forth above. The number of carbon atoms indicated (eg C _1-10 ) each independently refers to the number of carbon atoms in the alkyl or cycloalkyl moiety or in the alkyl portion of the macrosubstituent in which alkyl appears as the prefix root.

The term "oxo" relates to the substituent = O. The term "halogen" includes iodine, bromine, base and fluorine. The term "preterm birth" refers to the ectopic discharge of a surviving infant before the normal term of the pregnant woman, and more particularly to the beginning of labor due to cervical laxity and dilatation before the 37th week of the pregnant woman. It may or may not be accompanied by vaginal bleeding or membrane rupture.

The term "dysmenorrhea" means painful menstruation. The term "cesarean delivery" means an abdominal and uterine wall incision for fetal delivery. As used herein, the definition of each expression is independent of its definition elsewhere in the same structure, if it occurs more than once in that structure.

The ability of the compounds of formula I to antagonize oxytocin makes them useful as agents for the treatment and prevention of disorders involving oxytocin in mammals, especially humans. Examples of such disorders are preterm birth and especially dysmenorrhea. These compounds also have utility in arresting labor prior to Caesar delivery. Because of the known relationship of vasopressin to oxytocin, the compounds of the invention are also useful as vasopressin antagonists. They are useful in the treatment or prevention of medical conditions associated with vasopressin disorders, including their use as diuretics and their use in congestive heart failure.

The compounds of the present invention are administered in oral dosage forms such as tablets, capsules (each containing timed-release and sustained-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. be able to. Similarly, they are administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the desired compound is used as the birth control agent.

Dosage regimens utilizing the compounds of the present invention are used in patient type, species, age, weight, sex and medical condition; degree of condition to be treated; route of administration; patient renal and hepatic function; It will be selected according to a variety of factors including the specific compound or salt thereof. A normal physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, suppress or arrest the progress of the condition.

The oral dosage of the present invention is in the range of about 0.3-6.0 g / day orally when used for the indicating effect. The most preferred intravenous dose is 0.1-
It is in the range of about 10 mg / min. Advantageously, the compounds of the invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily. In addition, preferred compounds of the present invention may be administered in the topical nasal form of a suitable nasal vehicle or via the transdermal route using the form of transdermal patches well known to those of ordinary skill in that art. For administration in the form of transdermal delivery systems, dosing is, of course, continuous rather than intermittent during dosing.

In the method of the present invention, the compounds detailed herein are the active ingredients and have been appropriately selected with respect to the prescribed dosage form being consistent with conventional pharmaceutical practice of oral tablets, capsules, elixirs, syrups and the like. It will typically be administered with a suitable formulation diluent, excipient or carrier (collectively referred to herein as "carrier" material). For oral administration in the form of tablets or capsules, the active drug component is admixed with an orally non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. The disintegrant is not particularly limited and includes starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

The compounds of the present invention may be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from various phospholipids such as cholesterol, stearylamine or phosphatidylcholines.

The compounds of the present invention may be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may be coupled to soluble polymers as targetable drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylasparaginamide-phenol or polyethylene oxide polylysine substituted with palmitoyl residues. In addition, the compounds of the present invention are biodegradable polymers useful in achieving controlled release of drugs, such as polylactic acid, porepsilonecaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and It may be cross-linked to a hydrogel or coupled to an amphiphilic block copolymer.

The compounds of formula I are readily available starting materials,
It can be easily prepared according to the following reaction route and examples or modifications thereof using reagents and conventional synthetic procedures. Variants known per se to the person skilled in the art can also be used in these reactions, but are not mentioned in more detail.
Reference is also made to our co-pending U.S. patent application Ser. No. 488,343, filed March 2, 1990, the entire disclosure of which is incorporated herein by reference. Regarding the synthesis of indene and their 2-oxo derivatives to spiropiperidine analogs, Matier et al., Journal of Organic Chemistry, Vol. 36, No. 5,
Pp. 650-654, 1971 [Matier, et al., J.
Org. Chem., Vol. 36, No. 5, 650-654 (1
971)], the entire disclosure of which is incorporated herein by reference. Mathier et al., Journal
Of Organic Chemistry, Volume 36, Volume 5
A variation of this operation described in No. pp. 650-654, 1971 is also incorporated herein by reference.

Most preferred compounds of the present invention are any or all of the compounds specifically described in these examples. However, these compounds are not to be construed as forming the only type contemplated by the present invention, and any combination of the compounds or portions thereof may form a type by themselves. The following examples show further details regarding the preparation of compounds of the present invention. Those of ordinary skill in the art will readily understand that known variations of the conditions and processes of the following manufacturing operations can be utilized to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted.

[0038]

[Chemical 13]

[Chemical 14]

[Chemical 15]

[Chemical 16]

[Chemical 17]

[Chemical 18]

[Chemical 19]

[0039]

[Chemical 20]

[0040]

[Chemical 21]

[Chemical formula 22]

[Chemical formula 23]

[Chemical formula 24]

[0041]

[Chemical 12]

[Chemical 13]

[0042]

[Chemical 27]

[Chemical 28]

[0043]

[Chemical 29]

[0044]

[Chemical 30]

[Chemical 31]

[Chemical 32]

[Chemical 33]

[0045]

[Chemical 34]

[Chemical 35]

[Chemical 36]

[Chemical 37]

[Chemical 38]

[0046]

[Chemical Formula 39]

[0047]

[Chemical 40]

[0048]

[Chemical 41]

[Chemical 42]

[0049]

Example A

[Chemical 43] Endo- (1S) -1 '(((2-amino-7,7-dimethylbicyclo (2.2.1) -hepta-1-yl)-
Methyl) - sulfonyl) spiro (1H-indanyl down -1,
4'-piperidine) di-t-butyl dicarbonate (31 g, 0.14 mol
, Aldrich) and bis (2-chloroethyl) amine hydrochloric acid (21.6 g, 0.1
2 mol, Aldrich and CH ₂ Cl ₂ (25
0 ml), stirred at ambient temperature and treated with triethylamine (12.8 g, 0.127 mol) dropwise over 15 minutes. After 1 hour, another 1.5 ml of triethylamine was added. After a total of 2.5 hours, the mixture was
Pour onto a column of silica gel packed with CH ₂ Cl ₂ : hexane (1: 1) and elute with CH ₂ Cl ₂ . The combined product fractions are
Evaporation to dryness under reduced pressure gave N, N-bis (2-chloroethyl) -t-butyl-carbamate. Indene (1 mL) in dehydrated tetrahydrofuran (THF, 18 ml) cooled in an ice bath and placed under a nitrogen blanket.
To the 0.3 g, 89 mmol) solution was added lithium bis (trimethylsilyl) amide (Aldrich, 177 ml of a 1.0 M solution in THF; 177 mmol) over 15 minutes. The mixture was stirred in the cold for 30 minutes and then stirred in an ice bath of N, N-bis (2-chloroethyl) -t-butylcarbamate (21.2 g,
88 mmol) in a solution over 15 minutes. This mixture was cooled in a nitrogen environment for 2 hours and at room temperature for 30 hours.
It was stirred for a minute and then evaporated under reduced pressure to give a foam. CH ₂ Cl ₂
Was added and the resulting mixture was added to hexane 40 in CH ₂ Cl _2.
It was poured onto a silica gel column packed with the one containing%.
The column is a solution containing 40% hexane in CH ₂ Cl ₂ , then CH
Elute with ₂ Cl ₂ and evaporate the product fractions under reduced pressure to give 1′-
(T-Butyloxycarbonyl) -spiro (indene-
1,4'-piperidine) was obtained.

1- (t-Butyloxycarbonyl) spiro (indene-1,4'-) in ethyl acetate (250 ml)
The one containing piperidine) (16 g, 56 mmol) was stirred in an ice bath and saturated with HCl (g) for 30 minutes. The mixture was evaporated to dryness. Add ethyl acetate,
The residue was triturated under reduced pressure 3 times, the residue was triturated with diethyl ether and filtered to give spiro (1H-indene-1,4'-piperidine) hydrochloride. The free base was determined by slurrying the hydrochloride in aqueous sodium bicarbonate and extracting with CH ₂ Cl ₂ . The organic layer was separated, dried over sodium sulfate, filtered, and evaporated under reduced pressure to dryness. Spiro (1H
-Indene-1,4 'piperidine) was obtained. Spiro (1
H-indene-1,4'piperidine) (308 mg, 1.
66 mmol) and (+)-10-camphor-sulfonyl chloride (418 mg, 1.66 mmol) were combined in CH ₂ Cl ₂ and treated with triethylamine (0.23 ml). The mixture was stirred at ambient temperature for 15 minutes, then poured into a column of silica gel and eluted with 1: 1 CH ₂ Cl ₂ : hexane. The product fractions were combined, evaporated to dryness under reduced pressure, recrystallized from petroleum ether and dried under reduced pressure at ambient temperature overnight to give a solid (1S) -1'-
(((7,7-Dimethyl-2-oxobicyclo- (2.
2.1) Hept-1-yl) -methyl) sulfonyl) spiro (1H-indene-1,4′-piperidine) was obtained.

(1S)-in pyridine (500 ml)
1 '-(((7,7-Dimethyl-2-oxobicyclo-
(2.2.1) Hept-1-yl) methyl) sulfonyl) spiro (1H-indene-1,4′-piperidine)
A solution containing (30 g, 0.075 mmol) in an oil bath at 70
It was heated to ℃ (internal temperature). Hydroxyamine hydrochloric acid (30
g) was added in 3 portions over about 20 minutes. After 2 hours, another 10 g of hydroxylamine hydrochloric acid (10
Added over time). After 30 minutes, 40 minutes and 50 minutes, another 3 g of hydroxylamine hydrochloric acid was added. After a further 30 minutes, the mixture was poured into water (2 liters) and extracted 3 times with ethyl acetate (30 ml each). The organic layers are combined and 1N hydrochloric acid (total 600
ml), dried over sodium sulfate, filtered, and evaporated under reduced pressure to dryness. EtOH (anhydrous, about 250 ml)
Was added to the obtained thick syrup-like product, and the solution was allowed to stand at room temperature overnight. The mixture was filtered and the filtrate was boiled to about 80 ml. After standing, the mixture was filtered again and boiled to approximately 20 ml. Three
After the second filtration, the filtered solids are combined and (1S)
-1 '-(((7,7-dimethyl-2-oxyiminobicyclo- (2.2.1) hepti-1-yl) -methyl)
Sulfonyl) spiro (1H-indene-1,4′-piperidine) (28 g) was obtained.

In water, an activated Raney-nickel catalyst (about 30
The one containing g) was freshly prepared, left to stand and the water decanted. Absolute ethanol (300 ml) was added, the mixture was stirred and allowed to stand again. The solvent was decanted. Two more wash-decant repeats were similarly performed using 150 ml of ethanol. Absolute ethanol (450 ml) and 2-methoxyethanol (90
(1S) -1 '-(((7,7-
Dimethyl-2-oxyiminobicyclo- (2.2.1)
Hept-1-yl) methyl) sulfonyl) -spiro (1
H-indene-1,4'-piperidine) (30 g) was stirred, nitrogen gas was bubbled through this suspension / solution and Raney-Nickel catalyst was added. The mixture was hydrogenated at 50 psi overnight. TLC (9: 1 CH ₂ Cl ₂ : MeOH, silica gel) showed the reaction was complete. The catalyst was filtered off and the filtrate was evaporated under reduced pressure to dryness. This crude solid (27 g) was divided into 7 batches, each batch was dissolved in methylene chloride (about 200 ml), silica (700 g in a 100 mm column, 8% (v / v) in methylene chloride). Flash chromatograph on 200 ml of methanol), and elute 200 ml fractions. The exo-isomer of the title amine is in a fraction of about 5.7 and the desired endo-isomer is about 8-.
Obtained in 16 fractions. TLC was run on silica eluting with 8% methanol-methylene chloride and developed with phosphomolybdic acid. The product fractions were combined and evaporated to dryness to give the title compound as a colorless solid (4.5g from each 7g lot, total about 18g).

Example 1

[Chemical 44] Endo- (1S) -1 '-(((2- (but-3-ene-1-oilamino) 7,7-dimethyl-bicyclo (2.2.1) -hepta-1-yl) -methyl) sulfo
Nyl) spiro (1H-indane) -1,4'-piperidi
Endo-1S-1'- in methylene chloride (3 ml)
(((2-amino-7,7-dimethylbicyclo (2.
2.1) -Hept-1-yl) -methyl) -sulfonyl) spiro (1H-indan-1,4′-piperidine)
(50 mg, 0.000125 m) crotonyl chloride (13.1 mg, 14 ml, 0.
000125M) was added via syringe. After 2 minutes, triethylamine (50 ml) was added and the solution was made basic (pH
= 9). After 1 hour, the reaction mixture was concentrated and chromatographed on a silica "flash" column using the oil as solvent with 40% ethyl acetate in hexane. The 27-40 fraction contained fluorescent spots. These were concentrated, ether-hexane was added and concentrated to give the title compound as a white foam.
NMR (CDCL ₃ ) was consistent with the structure. HPLC: 210-97.181% 254-99.
386% Mass spectrum: Calculated value, m / e = 470.679 Measured value, m / e = 471.3 Analysis for C ₂₇ H ₃₈ N ₂ O ₃ S Calculated value: Carbon 68.90; Hydrogen 8.14; Nitrogen 5.95 Measured value: Carbon 68.99; Hydrogen 8.19; Nitrogen 5.7

Example 2

[Chemical formula 45] Endo- (1S) -1 '-(((2- (dimethylaminosulfonylamino) -7,7-dimethylbicyclo (2.
2.1) - hept-1-yl) methyl) - sul Honiru)
Spiro (1H-indan-1,4-piperidine) dry - heat-dried flask (50 ml volume) was used under a nitrogen environment to produce endo-1S-1 ′-(((2-amino-7,7-
Dimethylbicyclo (2.2.1) -hepta-1-yl)
-Methyl) -sulfonyl) -spiro (1H-indane-
1,4'-piperidine) (50 mg, 0.000125
M) was dissolved in methylene chloride (3 ml). Dimethylaminosulfonyl chloride (17.9 mg, 0.
000125M) was added and 2 minutes later triethylamine (50 ml) was added. After 1 hour, the reaction mixture was concentrated under reduced pressure (20 mm). Purify by silica "flash" column chromatography using methylene chloride (9) -methanol (1) as solvent, add hexane and concentrate to give the title compound as a brown solid. NMR (CDCL ₃ ) was consistent with the structure. HPLC: 210-96.47% 254-100% Mass spectrum: Calculated value 509.736 Measured value 510.3 Analysis for C ₂₅ H ₃₉ N ₃ O ₄ S ₂ ; Calculated value: Carbon 59.51; Hydrogen 7.93 Nitrogen 8.04 Measured value: Carbon 59.58; Hydrogen 7.71; Nitrogen 7.87

Example 3

[Chemical formula 46] Endo- (1S) -1 '-(((2- (ethoxycarbonylamino) -7,7-dimethylbicyclo (2.2.
1) - hept-1-yl) - methyl) - a sulfonyl) S
Pyro (1H-indan-1,4-piperidine) Dry - heat-dried flask (50 ml volume) was used under a nitrogen environment to produce endo-1S-1 ′-(((2-amino-7,7-
Dimethylbicyclo (2.2.1) -hepta-1-yl)
-Methyl) -sulfonyl) -spiro (1H-indane-
1,4'-piperidine) (50 mg, 0.000125
M) was dissolved in methylene chloride (3 ml). Ethyl chloroformate (13.6mg, 12ml, 0.00
0125M) was added via syringe. After 2 minutes, triethylamine (50 ml) was added to make the solution basic (pH = 9). After 30 minutes, the reaction mixture was concentrated under reduced pressure (20 mm). This oil was added to hexane as a solvent to obtain 40
Chromatographed on a silica "flash" column with% ethyl acetate. Product was contained in fractions 12-20. These fractions were concentrated under reduced pressure (20 mm). Hexane-ether was added to this oil,
Evaporation under reduced pressure gave 17 mg of the title compound as a white powder. NMR (CDCL ₃ ) was consistent with the structure. HPLC 210-9.817% 254-100
% Mass spectrum calculated value 474.668 measured value 475.3 analysis for C ₂₆ H ₃₈ N ₂ O ₄ S; calculated value; carbon 65.79: hydrogen 8.07: nitrogen 5.90 measured value; carbon 66.05: Hydrogen 8.22: Nitrogen 5.72

Example 4

[Chemical 47] Endo- (1S) -1 '-(((2- (2-thiophenecarbonylamino) -7,7-dimethylbicyclo (2.
2.1) - hept-1-yl) - methyl) - scan Ruhoni
) Spiro (1H-indan-1,4-piperidine) Dry - heat-dried flask (50 ml volume) was used, under a nitrogen environment, endo-1S-1 '-(((2-amino-7,7-
Dimethylbicyclo (2.2.1) -hepta-1-yl)
-Methyl) -sulfonyl) -spiro (1H-indane-
1,4'-piperidine) (50 mg, 0.000125
M) was dissolved in methylene chloride (3 ml). 2-
Thiophene carbonyl chloride (18mg, 13.4m
l, 0.000125 m) was added by syringe. Triethylamine (50 ml) was added to make the mixture basic. The reaction mixture was concentrated to an oil and chromatographed on a silica "flash" column using 40% ethyl acetate in hexane as the eluent. Product was contained in fractions 12-20. 1
Fractions 1-18 contained the desired product and were concentrated to an oil. Ether-hexane was added and removed to remove 27 mg of the title compound as a white amorphous solid.
Got HPLC 210-98.873% 254-97 /
931% Mass spectrum Calculated value 512.738 Measured value 513.3 C ₂₈ H ₃₆ N ₂ O ₃ S ₂ 0.72 Analysis for hexane: Calculated value: Carbon 63.97; Hydrogen 7.11; Nitrogen 5.33 measured Values: carbon 63.59; hydrogen 6.78; nitrogen 5.08.

Example 5

[Chemical 48] Endo- (1S) -1 '-(((2- (isonicotinoylamino) -7,7-dimethyl-bicyclo (2.2.
1) - hept-1-yl) - methyl) - a sulfonyl) S
Pyro (1H-indan-1,4-piperidine) Dry - heat-dried flask (50 ml volume) was used under a nitrogen environment to produce endo-1S-1 ′-(((2-amino-7,7-
Dimethylbicyclo (2.2.1) -hepta-1-yl)
-Methyl) -sulfonyl) -spiro (1H-indane-
1,4'-piperidine) (50 mg, 0.000125
M) was dissolved in methylene chloride (3 ml). Isonicotinoyl chloride dihydrochloride (22.3
8 mg, 0.000125 m) was added. After 2 minutes, triethylamine (50 ml) was added to bring the pH to 9. A "flash" in which the solvent is distilled off under reduced pressure and the product is used as solvent in methylene chloride (9) -methanol (1).
Purified on a silica column. The product was contained in fractions 6-10 and was concentrated. This oil was added to hexane-
Treated with ether and removed under reduced pressure. 18 mg of the title compound are obtained as a white foam. NMR (CDCL ₃ ) was consistent with the structure. HPLC 210-95.84% 254-98.0
4% mass spectrum calculated 507.7; measured 5
Analysis for 08.3 C ₂₉ H ₃₇ N ₃ O ₃ S Calculated: Carbon 68.61; Hydrogen 7.35; Nitrogen 8.28 Measured: Carbon 68.46; Hydrogen 6.99; Nitrogen 7.90.

Example 6

[Chemical 49] End - (1S) -1 '- (((2-(noradamantyl-1-carbonylamino) -7,7-dimethyl - bicyclo (2.2.1) - hept-1-yl) - methyltransferase) -
Sulfonyl) spiro (1H-indane-1,4-piperi
Gin) step: 1 noradamantyl-1-carbonyl chloride
In a round bottom flask (50 ml volume), noradamantyl carboxylate (20.
8 mg, 0.000125M) solution in a nitrogen environment at 0 ° C.
Oxalyl chloride (120 ml) was added via syringe. Dimethylformamide (7 ml) was added and the solution was stirred at 0 ° C for 15 minutes. The reaction mixture was warmed to room temperature and stirred for 45 minutes. Remove the solvent under reduced pressure (20 m
m) was distilled off. Methylene chloride was added twice and evaporated under reduced pressure. The acid chloride of the title compound was placed under high vacuum (0.05 mm) for 1 hour before use in the next step. Step 2: End- (1S) -1 '-(((2-
(Noradamantyl-1-carbonylamino) -7,7
-Dimethylbicyclo (2.2.1) -hepta-1-yl) -methyl) -sulfonyl) spiro (1H-indan-1,4'- piperidine) adamantyl-1-carbonyl chloride in methylene chloride (4 ml) Dissolve and End-1S-1'-
(((2-amino-7,7-dimethylbicyclo (2.
2.1) -hepty-1-yl) -methyl) -sulfonyl) spiro (1H-indan-1,4′-piperidine)
(50 mg, 0.000125 m) was added. After 2 minutes, triethylamine (100 ml) was added using a syringe. The solvent was evaporated under reduced pressure and the oil was chromatographed on silica with 40% ethyl acetate in hexane as the eluent. The product fractions were collected and concentrated to an oil, to which ether-hexane was added and removed to give an amorphous white solid. This allows
10 mg of the title compound was obtained. NMR (CDCL ₃ ) was consistent with the structure. HPLC 210-98.427% 254-100
% Mass spectrum calculated value, m / e 550.81 measured value, analysis for m / e 551.3C ₃₃ H ₄₆ N ₂ O ₃ S: calculated value: carbon 71.96: hydrogen 8.42: nitrogen 5.09 measurement Value: Carbon 71.57: Hydrogen 8.71: Nitrogen 4.77

Example 7

[Chemical 50] Exo- (1S) -1 '-(((2- (ethylsuccinoylamino) -7,7-dimethyl-bicyclo (2.2.
1) - hept-1-yl) - methyl) - sulfonyl) S
Exo- (1S) -1 'in pyro (1H-indan-1,4'-piperidine) methylene chloride (3 ml)
-(((2- (Amino) -7,7-dimethylbicyclo (2.2.1) -hepta-1-yl) methyl) -sulfonyl) spiro (1H-indan-1,4'-piperidine) (50 mg , 0.000125M) solution, succinyl chloride (20.6mg, 0.000125M),
Added under nitrogen blanket. After 2 minutes, triethylamine (50 ml) was added using a syringe. The pH of this solution was 9. After 15 minutes, a new spot was observed in the thin layer chromatogram (40% ethyl acetate in silica-hexane). The reaction mixture was concentrated and the oil was chromatographed on a silica "flash" column using 40% ethyl acetate as solvent.
The product was contained in the fractions 24-28. This fraction was collected and concentrated. Ether-hexane was added, and this was removed to obtain 21.3 mg of the title compound as a white powder. NMR
(CDCl ₃ ) was consistent with the structure. HPLC 210-99.190% 254-96.
914% Mass spectrum Calculated value m / e 530.732 Measured value m / e 531.5 C ₂₉ H ₄₂ N ₂ O ₅ S-Calculated value for 0.25 H ₂ O Calculated value Carbon 65.08: Hydrogen 8.00: Nitrogen 5.23 Measured value Carbon 65.16: Hydrogen 8.03: Nitrogen 5.09

Example 8

[Chemical 51] Endo- (1S) -1 '-(((2- (tetrazole-
1-Acetylamino) -7,7-dimethylbicyclo (2.2.1) -hepta-1-yl) -methyl) -sul
Honyl) -spiro (1H-indane-1,4-piperidi
N) Using a dry heat-dried flask (50 ml volume), under nitrogen, endo-1S-1 '-(((2-amino-7,7-dimethylbicyclo (2.2.1) -hepta-1-yl). ) -Methyl) -sulfonyl) -spiro (1H-indane-1,
4'-piperidine) (50 mg, 0.000125M),
Tetrazole-1-acetic acid (16 mg, 0.000125
M) and benzotriazol-1-yloxytris (dimethylamino) phosphonium-hexafluorophosphate (Sequalog) (55 mg, 0.000125
M) was dissolved in acetonitrile (3 ml). Diisopropylethylamine (50 ml) was added to make the solution basic. Thin layer chromatogram (silica-
A new spot was observed in methylene chloride (9) -methanol (1) and the reaction was concentrated to an oil. This oil was dissolved in methylene chloride-ether (1: 3) and the solution was washed with water, sodium bicarbonate (saturated, aq), water, 10% potassium acid sulfate, and brine. After dehydration with sodium sulphate, the solution was filtered, concentrated to an oil and chromatographed on a silica "flash" column using 10% methanol in methylene chloride.
The product was contained in fractions 5-10 and was collected and concentrated. Ether-hexane was added and then removed to give the title compound as a white powder. NMR (CDCl ₃ ) was consistent with the structure. HPLC: 210-98% 254-100% Mass spectrum: Calculated 513.679: _{Found, 513.3 C 26 H 36 N 6} O 3 Calcd for S · 0.25 H ₂ O: carbon 60.37 : Hydrogen 7.11: Nitrogen 16.25 Measured value: Carbon 60.28: Hydrogen 6.96: Nitrogen 16.18

Example 9

[Chemical 52] Endo- (1S) -1 '-(((2- (2-fluroylamino) -7,7-dimethylbicyclo (2.2.1)-
Hept-1-yl) - methyl) sulfonyl) S pyro (1
H- Indan- 1,4-piperidine) Dry - heat-dried flask (50 ml volume) was used, and under nitrogen, endo-1S-1 '-(((2-amino-7,7-dimethylbicyclo (2.2. 1) -Hept-1-yl) -methyl) -sulfonyl) -spiro (1H-indan-1,
4'-piperidine) (50 mg, 0.000125M)
Was dissolved in methylene chloride (3 ml) to give 2-fluroyl chloride (16.3 mg, 0.000125M).
Was added. After 2 minutes, triethylamine (150 ml) was added to bring the pH to 9. The solvent was evaporated under pressure and the product was purified by silica "flash" column using 40% ethyl acetate in hexane as solvent. The product was contained in fractions 6-10 and was concentrated. The oil was treated with hexane-ether and removed under reduced pressure. NMR (CDCl ₃ ) was consistent with the structure. HPLC: 210-99.341% 254-99.
576% mass spectrum calculated, 496.674; measured,
_{497.3 C 28 H 36 N 2 O} 4 Calcd for S: carbon 67.71; hydrogen 7.31; nitrogen 5.64 Found: carbon 67.41; hydrogen 7.39; nitrogen 5.46

Example 10

[Chemical 53] End- (1S) -1 '-(((2- (S- (1) -2
-Oxo-pyrrolidin-5-yl-carbonyl) amino) -7,7-dimethylbicyclo (2.2.1) -hepta-1-yl) -methyl) -sulfonyl) spiro (1H
-Indan-1,4- piperidine) Dry-heat-dried flask (50 ml volume) was used and under nitrogen, endo-1S-1 '-(((2-amino-7,7-dimethylbicyclo (2.2.1. ) -Hept-1-yl) -methyl) -sulfonyl) -spiro (1H-indan-1,
4'-piperidine) (50 mg, 0.000125M),
S- (1) -2-oxo-pyrrolidine-5-carboxylic acid (16.1 mg, 0.000125M) and benzotriazol-1-yloxytris (dimethylamino) phosphonium-hexafluorophosphate (sequalog)
(55 mg, 0.000125M) was dissolved in acetonitrile (3 ml). Diisopropylethylamine (50 ml) was added to make the solution basic. After thin layer chromatography (silica-methylene chloride (9) -methanol (1)) a new spot was observed and the reaction was concentrated to an oil. This oil was dissolved in methylene chloride-ether (1: 3) and the solution was treated with water, sodium bicarbonate (saturated, aqueous), water, 10
Wash with% acidic potassium bisulfate and brine. After dehydration with sodium sulfate, the solution was filtered and then concentrated to an oil. Ether-hexane was added and removed under reduced pressure to give the title compound as a white solid. NMR (CDCl ₃ ) was consistent with the structure. HPLC: 210-93.102% 254-92.
292% mass spectrum; calculated, 513.705; measured,
514.3

Example 11

[Chemical 54] End- (1S) -1 '-(((2- (L-N- (ter
t. -Butoxycarbonyl) -4-benzyloxy-prolinoylamino) -7,7-dimethylbicyclo (2.
2.1) -Hept-1-yl) -methyl-sulfonyl)
Using spiro (1H-Lee Ndan 1,4-piperidine) dry heat dried flask (50ml volume), under nitrogen,
Endo-1S-1 '-(((2-amino-7,7-dimethylbicyclo (2.2.1) -hepta-1-yl) -methyl) -sulfonyl) spiro (1H-indan-1,
4'-piperidine) (50 mg, 0.000125M),
L-N (tert.-butoxycarbonyl) -4-benzyloxy-proline (40.2 mg, 0.000125
M), and benzotriazol-1-yloxytris (dimethylamino) phosphonium-hexafluorophosphate (squalogue) (55 mg, 0.000125).
M) was dissolved in acetonitrile (3 ml). Diisopropylethylamine (50 ml) was added to make the solution basic. After thin layer chromatography (silica-methylene chloride (9) -methanol (1)) a new spot was observed and the reaction was concentrated to an oil.
This oil was converted into methylene chloride-ether (1:
Dissolve in 3) and wash the solution with water, sodium bicarbonate (saturated, aqueous), water, 10% potassium bisulfate and brine. After dehydration with sodium sulfate, the solution is filtered,
Concentrate to an oil and "flash" it with 40% ethyl acetate in hexane as solvent.
Purified by silica chromatography. The product is 15
It was contained in the -24 fraction and was collected and concentrated. Treatment with ether-hexane gave the title compound as a white solid. 10 mg of the sample was used for analysis and the rest was used for the next step. NMR (CDCl ₃ ) was consistent with the structure. HPLC: 210-99.003% 254-100
% Mass spectrum: Calculated value, 705.965: Measured value 706 C ₄₀ H ₅₅ N ₃ O ₆ S; Analysis value for 0.25 H ₂ O Calculated value Carbon 67.62 Hydrogen 7.87 Nitrogen 5.91 Measured value Carbon 67 .56 hydrogen 8.11 nitrogen 5.59

Example 12

[Chemical 55] End- (1S) -1 '-(((2- (L-N (tert _.
-Butoxycarbonyl) -4-hydroxy-prolinoylamino) -7,7-dimethylbicyclo (2.2.1)
-Hept-1-yl) methyl-sulfonyl) spiro (1
H-indan- 1,4-piperidine) endo- (1S) -1 '-(((2- (L-N (tert _.
-Butoxycarbonyl) -4-benzyloxy-prolinoylamino) -7,7-dimethyl) bicyclo (2.
2.1) -Hept-1-yl) -methyl) -sulfonyl) spiro (1H-indan-1,4-piperidine),
A mixture of ethanol (5 ml) and Pd (OH) ₂ (60 mg) was hydrogenated using a Parr apparatus at 50 psi for 18 hours. The catalyst was filtered off and the solvent was evaporated under reduced pressure to give the title compound as a white solid. NMR (CDCl ₃ ) was consistent with the structure. HPLC: 210-93.5% 254-97.38
1% mass spectrum calculated value, 615.840; measured value, analysis for 616 C ₃₃ H ₄₉ N ₃ O ₆ S ・ 1.5 H ₂ O calculated value carbon 61.65: hydrogen 8.15: nitrogen 6.53 measurement Value Carbon 61.46: Hydrogen 7.88: Nitrogen 6.90

Example 13

[Chemical 56] End - (1S) -1 '- ( ((2- (L-4- hydroxy - Pro Reno yl amino) -7,7-dimethyl-bicyclo (2.2.1) - hept-1-yl) - methylation - Sur
Honyl) spiro (1H-indan-1,4-piperidi
N) hydrochloride endo- (1S) -1 '-(((2- (L-N (tert _.
-Butoxycarbonyl) -4-hydroxy-propylamino) -7,7-dimethyl) bicyclo (2.2.1)-
A mixture of hept-1-yl) -methyl) -sulfonyl) spiro (1H-indan-1,4-piperidine),
It was dissolved in ethyl acetate (5 ml) and cooled to -5 ° C. This was placed in a nitrogen environment, and hydrochloric acid gas was bubbled for 10 minutes. The solvent was distilled off under reduced pressure. Ether was added and then removed under reduced pressure 15.48 mg of the title compound as a white solid.
Got NMR (CDCl ₃ ) was consistent with the structure. HPLC: 210-93.50% 254-93.8.
12% Mass spectrum: Calculated value 515.721 (free base) Measured value 516.4 Analysis for C ₂₈ H ₄₁ N ₃ O ₄ S HCl 0.25 H ₂ O Calculated value: Carbon 60.41: Hydrogen 7.69: Nitrogen 7.54 Measured value: Carbon 60.08: Hydrogen 7.73: Nitrogen 7.35

Example 14

[Chemical 57] Endo- (1S) -1 '-(((2- (3-indoleacetylamino) 7,7-dimethyl-bicyclo (2.
2.1) - hept-1-yl) methyl - a sulfonyl) S
Pyro (1H-indan-1,4-piperidine) Dry - heat-dried flask (50 ml volume) was used and under nitrogen, endo-1S-1 ′-(((2-amino-7,7-dimethylbicyclo (2. 2.1) -Hept-1-yl) -methyl) -sulfonyl) spiro (1H-indan-1,4 ′
-Piperidine) (50 mg, 0.000125M), 3-
Indole acetic acid (21.9 mg, 0.000125M) and benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (Sequalog) (55 mg, 0.000125M) were dissolved in acetonitrile (3 ml). Diisopropylethylamine (50 ml) was added to make the solution basic. After thin layer chromatography (silica-methylene chloride (9) -methanol (1)) a new spot was observed and the reaction was concentrated to an oil. This oil was dissolved in methylene chloride-ether (1: 3) and the solution was washed with water, sodium bicarbonate (saturated, aq), water, 10% potassium bisulfate and brine.
After dehydration with sodium sulphate, the solution is filtered and concentrated to an oil which is then "flashed" using a solution of 10% methanol in methylene chloride as solvent.
Purified by silica chromatography. The product is 12
It was contained in the -19 fraction and was collected and concentrated. Treatment with ether-hexane gave the title compound as a white solid. NMR (CDCl ₃ ) was consistent with the structural formula. HPLC: 210-9.829% 254-92.
699% Mass spectrum: Calculated value 559.777; Measured value 560.3 Analysis for C ₃₃ H ₄₁ N ₃ O ₃ S .0.5 H ₂ O Calculated value: Carbon 69.69; Hydrogen 7.44; Nitrogen 7. 51 Measured value: carbon 69.70; hydrogen 7.57; nitrogen 7.20

Example 15

[Chemical 58] End- (1S) -1 '-(((2- (S-3- (tert
-Butoxycarbonyl) amino) -2-oxo-1-pyrrolidineacetylamino) 7,7-dimethylbicyclo-
(2.2.1) Hept-1-yl) -methyl-sulfonyl) spiro (1H -indan-1,4-piperidine) Dry - heat-dried flask (50 ml volume) was used under nitrogen and endo-1S-. 1 '-(((2-amino-7,7-dimethylbicyclo (2.2.1) -hepta-1-yl) -methyl) -sulfonyl) spiro (1H-indane-1,4'
-Piperidine) (50 mg, 0.000125M), S-
3-((tert-Butoxycarbonyl) amino) -2-oxo-1-pyrrolidineacetic acid (32.2 mg, 0.0001
25M) and benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (Sequalog) (55mg, 0.000125)
M) was dissolved in acetonitrile (3 ml). Diisopropylethylamine (50 ml) was added to make the solution basic. After thin layer chromatography (silica-methylene chloride (9) -methanol (1)) a new spot was observed and the reaction was concentrated to an oil. This oil was converted to methylene chloride-ether (1:
Dissolve in 3) and wash the solution with water, sodium bicarbonate (saturated, aqueous), water, 10% potassium bisulfate and brine. After dehydration with sodium sulfate, the solution is filtered,
Concentrated to an oil which was purified by "flash" silica chromatography using 10% methanol in methylene chloride as the solvent. The product is
It was contained in fractions 15-28 and was collected and concentrated. Treatment with ether-hexane gave the title compound as a white solid. NMR (CDCl ₃ ) was consistent with the structural formula. HPLC: 210-94.005% 254-96.
33% Mass spectrum: Calculated value m / e, 642.859 Measured value m / e, 643.4 C ₃₄ H ₅₀ N ₄ O ₆ S-Analysis for 0.1 hexane Calculated value: Carbon 63.79: Hydrogen 7. 95: Nitrogen 8.59 Measured value: Carbon 63.66: Hydrogen 8.32: Nitrogen 8.29

Example 16

[Chemical 59] Endo- (1S) -1 '-(((2- (S-3-amino) -2-oxo-1-pyrrolidine-acetylamino)
7,7-Dimethylbicyclo (2.2.1) -hepta-1
- yl) - methyl) - sulfonyl) spiro (1H-indan-1,4-Hoon Perijin) hydrochloride end -1S-1 '- ((( 2- (S-3- (tert- butoxy carbonate sulfonyl) amino) - 2-oxo-1-pyrrolidineacetylamino) -7,7-dimethylbicyclo (2.2.1) hept-1-yl) -methyl) -sulfonyl) spiro (1H-indan-1,4′-piperidine) It was dissolved in ethyl acetate (5 ml) and cooled to -5 ° C. This was placed in a nitrogen environment and hydrochloric acid gas was bubbled through for 10 minutes. The solvent was distilled off under reduced pressure. Ether was added and then removed under reduced pressure to give 23.7 mg of the title compound as a white solid. NMR (CDCl ₃ ) was consistent with the structural formula. HPLC: 210-96.562% 254-95.
493% Mass spectrum: Calculated value for free base m / e 542 Measured value m / e 543.3 Analysis for C ₂₉ H ₄₂ N ₄ O ₄ S.H ₂ O.HCl Calculated value: Carbon 58.32: Hydrogen 7. 59: Nitrogen 9.38 Measured value: Carbon 58.14: Hydrogen 7.97: Nitrogen 9.21

Example 17

[Chemical 60] Step 1; endo- (1S) -1 '-(((2- (L-N-tert-
Butoxycarbonyl-histidinoylamino) -7,7
-Dimethylbicyclo (2.2.1) -hepta-1-yl) -methyl-sulfonyl) spiro (1H-indane-
1,4 piperidyl down) dry heat with dry flask (50ml volume), under nitrogen, end -1S-1 '- ((( 2- amino-7,7-dimethyl-bicyclo (2.2.1) hepta -1-yl) -methyl) -sulfonyl) spiro (1H-indan-1,4 '
-Piperidine) (50 mg, 0.000125M), L-
N-tert-butoxycarbonylhistidine (29.9m
g, 0.000125M) and benzotriazole-1
-Yloxytris (dimethylamino) phosphonium hexafluorophosphate (Sequalog) (55 mg,
0.000125M) was dissolved in acetonitrile (3 ml). Diisopropylethylamine (50 ml) was added to make the solution basic. Thin layer chromatograph (silica-methylene chloride (9) -methanol (1))
After a new spot was observed and the reaction was concentrated to an oil. This oily substance was converted to methylene chloride-
Dissolve in ether (1: 3) and wash the solution with water, sodium bicarbonate (saturated, aq), water, 10% potassium bisulfate and brine. After dehydration over sodium sulfate, the solution was filtered and concentrated to an oil which was purified by "flash" silica chromatography using 10% methanol in methylene chloride as the solvent. The product was contained in fractions 15-28, they were collected and concentrated. Treated with ether-hexane,
The title compound was obtained as a white solid. NMR (CD ₃ OD) was consistent with the structure. HPLC: 210-97.822% 254-100
% Mass spectrum: Calculated value m / e 639.859 Measured value m / e 640.3

Step 2: End- (1S) -1'-
(((2- (L-N-Histidinoylamino) -7,7
- dimethyl bicyclo (2.2.1) - hept-1-yl) - methyl) - sulfonyl) spiro (1H-indan-1,4-piperidyl down) end - (1S) -1 '- (((2- (L-N-tert-
Butoxycarbonylhistidinoylamino) -7,7-
Dimethylbicyclo (2.2.1) -hepta-1-yl)
-Methyl) -sulfonyl) spiro (1H-indane-
1,4'-piperidine) (50 mg, 0.000125
M) was dissolved in ethyl acetate (5 ml) and cooled to -5 ° C. This was placed in a nitrogen environment, and a hydrochloric acid gas was bubbled for 10 minutes. The solvent was distilled off under reduced pressure. Ether was added and then removed under reduced pressure to give 27.5 mg of the title compound as a white solid. NMR (CD ₃ OD) was consistent with the structural formula. HPLC: 210-98.652% 254-100
% Mass spectrum: Calculated value as free base m / e 539.7 Measured value m / e 540.3 Analysis for C ₂₉ H ₄₁ N ₅ O ₃ S 2HCl 2H ₂ O: Calculated value: Carbon 53.69: Hydrogen 7.30: Nitrogen 10:79 Measured value: Carbon 53.58: Hydrogen 7.45: Nitrogen 11.00

Example 18

[Chemical formula 61] End- (1S) -1 '-(((2- (D-N- (tert
-Butoxycarbonyl) -im-benzylhistidinoylamino) -7,7-dimethylbicyclo (2.2.1)
-Hept-1-yl-methyl) sulfonyl) spiro (1
H-Indan-1,4'- piperidine) Dry-heat-dried flask (50 ml volume) was used, and under nitrogen, endo-1S-1 '-(((2-amino-7,7-dimethylbicyclo (2.2 .1) -Hept-1-yl) -methyl) -sulfonyl) spiro (1H-indan-1,4 ′
-Piperidine) (50 mg, 0.000125M), D-
N-tert-butoxycarbonyl-im-benzyl-bistidine (43 mg, 0.000125M) and benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (Sequalog)
(55 mg, 0.000125M) was dissolved in acetonitrile (3 ml). Diisopropylethylamine (5
0 ml) was added to make the solution basic. After thin layer chromatography (silica-methylene chloride (9) -methanol (1)) a new spot was observed and the reaction was concentrated to an oil. This oil was dissolved in methylene chloride-ether (1: 3) and this solution was added to water,
Wash with sodium bicarbonate (saturated, aq), water, 10% potassium bisulfate and brine. After dehydration over sodium sulfate, this solution was filtered and concentrated. Ether-hexane gave the title compound as a white solid. NMR (CDCl ₃ ) was consistent with the structural formula. HPLC: 210-99.551% Mass spectrum Calculated value, m / e 730.062 Measured value, m / e 730.6 C ₄₁ H ₅₅ N ₅ O ₅ S ・ 0.65H ₂ O ・ 0.4 Analysis for hexane Calculated: Carbon 67.15: Hydrogen 8.04: Nitrogen 9.02 Carbon 67.18: Hydrogen 7.73: Nitrogen 9.02

Example 19

[Chemical formula 62] End - (1S) -1 '- (((2-(D-im - benzyl histidinol alkanoylamino) -7,7-dimethyl-bicyclo (2.2.1) - hept-1-yl) - methylation) −
Rufonyl) spiro (1H-indan-1,4-piperidi
N) hydrochloride endo- (1S) -1 '-(((2- (D-N (tert-
Butoxycarbonyl) -im-benzylhistidinoylamino) -7,7-dimethylbicyclo (2.2.1)-
Hept-1-yl) -methyl) -sulfonyl) spiro (1H-indan-1,4'-piperidine) was dissolved in ethyl acetate (5 ml) and cooled to -5 ° C. This was placed in a nitrogen environment and hydrochloric acid gas was bubbled for 10 minutes. The solvent was distilled off under reduced pressure. Ether was added and then removed under reduced pressure to give the title compound as a white solid. NMR (CDCl ₃ ) is
Consistent with the structural formula. HPLC: 210-100% Mass spectrum: Calculated value m / e 629.8879 Measured value m / e 630 C ₃₆ H ₄₇ N ₅ O ₃ S.HCl.0.1 Ethyl acetate.1.4H ₂ O
Calculated value for carbon 59.33: hydrogen 7.20: nitrogen 9.51 measured value carbon 59.36: hydrogen 7.03: nitrogen 9.50

Example 20

[Chemical formula 63] End- (1S) -1 '-(((2- (S-3-tert-
Butoxycarbonylamino-2-oxo-1-azepineacetylamino) -7,7-dimethylbicyclo (2.
2.1) -Hept-1-yl) -methyl-sulfonyl)
Spiro (1H-Lee Ndan 1,4-piperidine) dry heat dried using a flask (50ml volume), under nitrogen, end -1S-1 '- ((( 2- amino-7,7-dimethyl-bicyclo (2 1.2.1) -Hept-1-yl) -methyl) -sulfonyl) spiro (1H-indan-1,4 ′
-Piperidine) (50 mg, 0.000125M), S-
3-tert-butoxycarbonylamino-2-oxo-1
-Azepine acetic acid (32.8 mg), and benzotriazol-1-yloxytris (dimethylamino) phosphonium-hexafluorophosphate (sequalog) (5
5 mg, 0.000125M, acetonitrile (3 m
dissolved in l). Diisopropylethylamine (50m
l) was added to make the solution basic. After thin layer chromatography (silica-methylene chloride (9) -methanol (1)) a new spot was observed and the reaction was concentrated to an oil. This oil was dissolved in methylene chloride-ether (1: 3) and this solution was added to water, sodium bicarbonate (saturated, aqueous) water, 10%.
Wash with potassium bisulfate and brine. After dehydration over sodium sulfate, the solution was filtered and concentrated to an oil which was purified by "flash" silica chromatography using 10% methanol in methylene chloride as the solvent. Fractions containing product were collected and concentrated. Treatment with ether-hexane gave the title compound as a white solid. A 10 mg sample was saved for analysis. NMR (CDCl ₃ ) was consistent with the structural formula. HPLC 210-100% mass spectrum calculated m / e 670.918,
Analysis for 671 C ₃₆ H ₅₄ N ₄ O ₆ S Calculated: Carbon 64.44; Hydrogen 8.11; Nitrogen 8.35 Measured: Carbon 64.12; Hydrogen 8.23; Nitrogen 8.03

Example 21

[Chemical 64] Endo- (1S) -1 '-(((2- (S-3-amino-2-oxo-1-azepineacetylamino) -7,7
-Dimethylbicyclo (2.2.1) -hepta-1-yl-methyl) -sulfonyl) spiro (1H-indane-
1,4' piperidyl down) hydrochloride End - (1S) -1 '- ( ((2- (S-3-tert-
Butoxycarbonylamino-2-oxo-1-azepineacetylamino) -7,7-dimethylbicyclo- (2.
2.1) -Hept-1-yl) methyl) -sulfonyl)
Spiro (1H-indan-1,4'-piperidine) was dissolved in ethyl acetate (5 ml) and cooled to 5 ° C. This was placed under a nitrogen atmosphere and hydrogen chloride gas was bubbled for 10 minutes. The solvent was removed under reduced pressure. Ether was added and removed under reduced pressure to give the title compound as a white solid. NMR (CDCl ₃ ) was consistent with the structure. HPLC 210-100% mass spectrum: calculated value m / e, 570.802; measured value m / e, 571 elemental analysis C ₃₁ H ₄₆ N ₄ O ₄ S .HCl ・ 1.10 H ₂ O 0.4
0 Ethyl acetate: Calculated: C, 59.11; H, 7.97; N, 8.46 Found: C, 59.09; H, 8.00; N, 8.45.

Example 22

[Chemical 65] Endo- (1S) -1 '-(((2- (4-imidazoleacetylamino) -7,7-dimethylbicyclo (2.
2.1) - hept-1-yl) - methyl) - sul Honi
Le) Spiro (1H-indan-1,4'-piperidine)
Hydrochloride N, N-bis (2-chloroethyl) -t-butylcarba
Formate di -t- butyl dicarbonate (62 g, 0.28 mol, available from Aldrich (Aldrich) (Co.)) and bis (2-chloroethyl) amine hydrochloride (55 g, 0.2
1 mol, available from Aldrich Co.) was stirred together in methylene chloride (400 ml). Triethylamine (42 ml, 0.3 mol) was added dropwise but rapidly to the stirred suspension. After 10 minutes, additional triethylamine (approximately 5-6 ml) was added and the pH of the mixture was adjusted to pH (as measured by the spot of the sample wetted with water, E. Merch pH5-10 colorpHast stick).
Adjusted to 9 to 9.5. The mixture was stirred for 1 hour at ambient temperature then filtered. Divide the filtrate into halves and load each half (approximately 300 ml) with 3: 2 (v: v) methylene chloride: hexane onto a silica column about 38 cm (15 inches) long and 5 cm (2 inches) in diameter for separation. Flash chromatography with 9: 1 methylene chloride:
Elute with hexane. Fractions of 100 ml were collected and product was obtained in approximately fractions 6-12. The assay was by TLC on silica gel plates, eluting with methylene chloride and visualized by phosphomolybdic acid color development (Rf value approximately 0.75). The product fractions from both columns were combined and concentrated in vacuo to give the title compound as a colorless oil (70
g) was obtained. The oil was dissolved twice in dry THF and concentrated under vacuum to remove methylene chloride.

[0077] 1 '- (t-butyloxycarbonyl) spiro (1H-indene-1,4'-piperid-lysine) is cooled in an ice bath and dry tetrahydrofuran (THF, 40 ml) maintained under a nitrogen blanket during the A solution of indene (36.2 g, 310 mmol) was charged with lithium bis (trimethylsilyl) -amide (1.0 in THF).
M solution 620 ml; 620 mmol, Aldrich Co.
(Available from Co., Ltd.) was added (using a dropping funnel). Mix 3
Stir for 0 min at low temperature, then N, N in THF (40 ml)
A solution of -bis (2-chloroethyl) -t-butylcarbamate (70 g, 290 mmol) was cannula transferred over 20 minutes and stirred in an ice bath. The mixture was stirred cold for 2 hours and under nitrogen at ambient temperature for 30 minutes then evaporated under vacuum to a foam. CH ₂ Cl ₂ (400 ml) was added and the resulting mixture was split in half. Each half is a silica gel column [about 38 cm (15 inches), inner diameter about 5
cm (2 inches)] was injected with 1: 1 hexane: CH ₂ Cl ₂ (2 liters) followed by 1: 4 hexane: CH ₂ Cl ₂ to elute. The product fractions (200 ml fractions 3-9) were evaporated to dryness under vacuum to give 1 '-(t-butyroxycarbonyl) spiro (indene-1,4'-piperidine) as a yellow crude solid. ), A total of 90 g was obtained. The solid was dissolved in boiling hexane (400 ml), cooled and the crystalline solid filtered. The filtrate was repeatedly boiled down to 1/2 volume, cooled and filtered to obtain a secondary product. A total of 54 g of pure product was obtained. The residue was rechromatographed to give an additional 6.7 g (60.7 g total).

Spiro (1H-indene-1,4'-pipet
Lysine) hydrochloride 1 '-(t-butyloxycarbonyl) spiro (indene-1,4'-piperidine) in ethyl acetate (700 ml)
(60.7 g) was stirred in an ice bath and saturated with HCl (gas) for 30 minutes while keeping the internal temperature below 12 ° C.
The mixture was stirred at low temperature for a further 30 minutes and evaporated to dryness.
The ethyl acetate addition and vacuum removal was repeated 3 times and the residue was triturated with diethyl ether and filtered to give spiro (1H-indene-1,4'-piperidine) hydrochloride.

(1S) -1 '-(((7,7-Dimethyl-2-oxobicyclo (2.2.1) hept-1-yl) methyl) -sulfonyl) spiro (1H-indene-
1,4'- piperidine) spiro (1H-indene-1,4'-piperidine) hydrochloride (45.4 g, 0.2 mol) and (+)-10-camphorsulfonyl chloride (62.5 g, 0. 25 mol, available from Aldrich Co., Ltd. in CH ₂ Cl ₂ (70
0 ml) and mixed with triethylamine (68.5 ml,
0.5 mol). Further triethylamine was added as needed to adjust the pH value of the mixture to 9 to 9.5.
stick). The mixture is stirred at ambient temperature for 1 hour, then
Pour into a silica gel column [approximately 25 cm (10 inches), inner diameter approximately 5 cm (2 inches)] packed with CH ₂ Cl ₂ and inject 1: 1 Et ₂
O: eluting with CH ₂ Cl _2. The product fractions were combined and evaporated to dryness in vacuo to give the title compound as a solid. It was recrystallized from petroleum ether and dried under vacuum at ambient temperature for 6 hours: (mp 146-147 ° C). TLC: Rf = 0.44 on silica gel (CH ₂ Cl ₂₎ NMR: Consistent with structure HPLC: 99.7% pure or more MS: m / in e -399 molecular ion elemental analysis C ₂₃ H ₂₉ NO ₃ S: Calculated: C, 69.14; H, 7.32; N, 3.51 Found: C, 68.97; H, 7.2; N, 3.38.

(1S) -1 '-(((7,7-Dimethyl-2-oxyiminobicyclo (2.2.1) hept-1
-Yl) -methyl) sulfonyl) spiro (1H-indene- 1,4'-piperidine) piperidine (500 ml) in (1S) -1'-
(((7,7-Dimethyl-2-oxobicyclo (2.
2.1) Hept-1-yl) methyl) sulfonyl) spiro (1H-indene-1,4′-piperidine) (30
g, 0.075 mol) was heated to 70 ° C. (internal) in an oil bath. Hydroxylamine hydrochloride (30 g) was added in 3 portions over approximately 20 minutes. Two hours later,
Another 10 g of hydroxylamine hydrochloride was added (over 10 minutes). After an additional 30, 40 and 50 minutes, an additional 3 g of hydroxylamine hydrochloride was added. After a further 30 minutes, the mixture was poured into water (2 liters) and extracted 3 times with ethyl acetate (300 ml each). Combine the organic layers and wash with 1N HCl (total 600 ml),
Dry over sodium sulfate, filter and evaporate to dryness in vacuo. EtOH (anhydrous; approx. 250 ml) was added to make a thick syrup. The solution was left at ambient temperature overnight.
The mixture was filtered and the filtrate was boiled down to approximately 80 ml. After standing, the mixture was filtered again and boiled down to approximately 20 ml. After filtering 3 times, the filtered solids were combined to give the title compound (28 g).

Endo- (1S) -1 '(((2-amino-7,7-dimethylbicyclo (2.2.1) hept-1
-Yl) -methyl) sulfonyl) spiro (1H-indan- 1,4'-piperidine) freshly prepared activated Raney-nickel catalyst (approximately 3
0 g) was settled in water and the water was decanted. Absolute ethanol (300 ml) was added and the mixture was swirled and settled again. The solvent was decanted. Two more washing-decantation cycles were performed with 150 ml of ethanol. (1S) -1 '(((7,7
-Dimethyl-2-oxyiminobicyclo (2.2.1)
Hept-1-yl) methyl) sulfonyl) spiro (1H
-Indene-1,4'-piperidine) (30 g) was added to absolute ethanol (450 ml) and 2-methoxyethanol (9).
(00 ml) with stirring, nitrogen was bubbled through the suspension / solution and Raney-Nickel catalyst was added. Mix the mixture to about 3.
Hydrogenated under 5 kg / cm ² (50 psi) overnight. TLC
(9: 1 CH ₂ Cl ₂ : MeOH, silica gel) showed the reaction was complete. The catalyst was removed by filtration and the filtration was evaporated to dryness in vacuo. The crude solid (27g) was divided into 7g batches, each batch containing methylene chloride (approximately 200m2).
l) and flash chromatographed on silica (700 g in a 100 mm column, eluting with 8% methanol (v / v) in methylene chloride), 2
A 00 ml fraction was collected. The exo isomer of the title amine was obtained in fractions approximately 5-7 and fractions approximately 8-16 in the desired endo isomers. TLC on silica, eluted with 8% methanol / methylene chloride and confirmed by phosphomolybdic acid stain. The combined product fractions were evaporated to dryness to give the title compound as a colorless solid (4.5g from each 7g lot, approximately 18g total).

Endo- (1S) -1 '(((2-4-imidazoleacetylamino) -7,7-dimethylbicyclo- (2.2.1) -hept-1-yl) methyl) sulu > Honyl ) spiro (1H-indan-1,4'-piperidi
) Hydrochloride endo- (1S) -1 '(((2-amino-7,7-dimethylbicyclo- (2.2.1) hept-1-yl) methyl) sulfonyl) spiro (1H-indan-1 , 4 '
-Piperidine) 4.56 g (11.3 mmol) 50
Dissolve in ml DMF and the solution is 4-imidazole acetic acid.2.
30 g (14.1 mmol), 1-hydroxybenzotriazole hydrate (HBT) 1.9 g (14.1 mmol), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide HCl (EDC) 2. 7 g (1
(4.1 mmol). The pH of the suspension was adjusted to 9.5 with 4.65 ml (33.4 mmol) triethylamine and the reaction mixture was stirred at 25 ° C. for 18 hours. DMF was removed in vacuo and the crude purple residue was treated with water and extracted with EtOAc (3 times). Combine the organics, wash with H ₂ O (1 ×), brine (1 ×), dry over Na ₂ SO ₄ , filter,
Dried in vacuo. The crude product was subjected to silica gel flash chromatography (CH ₂ Cl ₂ / MeOH / conc. NH ₄ OH, 114/10).
5.29 g of the desired product as a white foam over 1)
(92%) was obtained. 5.17 g (10.1 mmol) of this product was dissolved in 100 ml of EtOAc. A solution of HCl (gas) in EtOAc was added dropwise with vigorous stirring until precipitation was complete. Slightly sticky mixture at 25 ° C
Stirred at rt for 15 min then evaporated to dryness in vacuo. Residue
Re-removed from EtOAc 3 times and then Et ₂ O twice. The white solid was stripped from the flask wall and triturated with Et ₂ O, collecting 5.3 g of the hydrochloride salt. Melting point: 93-167 ° C (slowly foaming) HPLC: 99.4% NMR: Consistent with structure, +0.30 ethyl acetate, 0.05
Ether and water. M. S. : M + H + 551 (FAB) Elemental analysis C ₂₈ H ₃₈ N ₄ O ₃ S ・ HCl ・ 0.30 C ₄ H ₈ O ₂・
0.05 C ₄ H ₁₀ O.0.4 H ₂ O (molecular weight 584.48) Calculated value: C, 60.41; H, 7.36; N, 9.59 Measured value: C, 60.38; H, 7.46; N, 9.33

Example 23

[Chemical formula 66] 1-[[6-Bromo-1,7-dimethyl-2-oxobicyclo [2.2.1] hept-7-yl) methyl] sulfonyl] -spiro [1H-indene- 1,4'-piperi
Zin] 100 mg of (+)-3-bromocamphosulfonic acid ammonium salt (0.304 mM) was dissolved in 15 ml of DLM. SOCl ₂ (FW = 118.97; d = 1.631;
1.52 mM; 120 ml) 5 equivalents were added. The mixture was reacted overnight, then concentrated to give crude sulfonyl chloride 92.
7 mg was obtained. 92.7 mg of sulfonyl chloride was added to dry THF2.
Dissolved in 5 ml. Indene salt (68.59mg)
1.1 equivalents and 2 equivalents of TFA were added and reacted at room temperature for 3 hours. The product was concentrated HCl, and washed with H ₂ O and brine. Flash chromatography with 20% EtOAc / petroleum ether. HPLC 97.7% at 13.52 minutes

Example 24

[Chemical formula 67] (1R-Syn) -1 ′-[[(1,7-dimethyl-2-
Oxobicyclo [2.2.1] hept-7-yl) methyl) sulfonyl] -spiro [1H-indene-1,4 '
- piperidine] glacial acetic acid (10ml) the product of Example 23 in (107 mg,
0.300 mmol) in a solution of zinc dust (24 mg, 0.3
67 mmol) was added. The temperature was then raised to reflux. After 30 minutes, the mixture was cooled to room temperature, filtered and then concentrated under reduced pressure. Purification by flash chromatography (35% ethyl acetate in petroleum ether as eluent) gave 80 mg of product as a white amorphous foam. N
MR (300 MHz, CDCl ₃ ): Consistent with structure HPLC (Vydac C18 column, 0.1% TFA in H ₂ O
/ CH ₃ CN 95/5 to 0/100 gradient, 15 minute gradient,
Flow rate = 1.5 ml / min): Purity = 98%, r. t. = 1
2.67 minutes FABMS: 400.91 [M + 1] ⁺ elemental analysis C ₂₃ H ₂₉ NO ₃ S: calculated value: C, 69.13; H, 7.32; N,
3.51 Found: C, 69.25; H, 7.30;
N, 3.48

Example 25

[Chemical 68] (1S) -1 ′ (((2- (trifluoromethyl) sulfonyl) oxy) 2,3-en-7,7-dimethylbicyclo (2.2.1) hept-1-yl) methyl) sulfo
Nyl) -spiro (1H-indene-1,4'-piperidi
Emissions) CH ₂ Cl ₂ (25 ml) solution of (1S) -1 (((7,7-dimethyl-2-bicyclo (2.2.1) hept-1-yl)
Methyl) sulfonyl) spiro (1H-indene-1,
4'-piperidine) (2 g, 5.0 mmol) and 2,6-di-tert-butyl-4-methylpyridine (1.
To a solution of 5 g, 7.5 mmol) triflic anhydride (1.3 ml, 7.5 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The mixture was then diluted with CH ₂ Cl ₂ (30 ml) and filtered. The filtrate is then 5
% HCl (2 × 50 ml), saturated NaHCO ₃ (2 × 50 ml),
And washed with brine, dried over Na ₂ SO ₄ and evaporated. Crude triflate in 20% hexane
Purify by flash chromatography eluting with% ethyl acetate to give the title product 1.7 as a white foam.
g (64%) was obtained. HPLC RT = 12.75 min NMR (CDCl ₃ ) Consistent with title compound FAB MS: 532 (M + 1) Elemental analysis C ₄₂ H ₂₈ NS ₂ O ₅ F ₃ : Calcd: N, 2.63; C, 54. 22; H, 2.63 Found: N, 2.37; C, 54.42; H, 5.34.

Example 26

[Chemical 69] (1S) -1 '-(((2- (dimethylphosphonyl) oxy) 2,3-ene-7,7-dimethylbicyclo (2.
2.1) hept-1-yl) sulfonyl) methyl spin
B) 1H-indene-1,4'-piperidine) The triflate product of Example 25 (50 mg, 0.097 mmol) in DMF (3 ml), dimethyl phosphite (13 ml, 0.14 mol), triethylamine. (61m
1, 0.44 mmol) and tetrakis (triphenylphosphine) palladium (5 mg, 0.005 mmol) were stirred under an argon atmosphere for 1 hour. The reaction was diluted with CHCl ₃ (25 ml). Chloroform 5%
It was washed with HCl (2 × 25 ml) and brine, dried over Na ₂ SO ₄ and evaporated to dryness. Purification by flash chromatography (25% ethyl acetate in hexane) gave 40 mg (86%) of the title compound as a white solid. HPLC RT = 10.31 min NMR (CDCl ₃ ) Consistent with title compound FAB MS: 492 (M + 1) Elemental analysis C ₂₅ H ₃₄ NSO ₅ P .0.5 H ₂ O Calculated value: N, 2.80; C , 59.99; H, 7.05 Found: N, 2.71; C, 59.90; H, 7.49.

Example 27

[Chemical 70] [1-[[[[exo-2-hydroxy-7,7-dimethyl-1- [spiro [1H-indene-1,4-piperidin] -1-yl-sulfonyl) methyl] bicyclo]
2.2.1] hept-2-yl] methyl] amino] carbonyl] -3- (main Chiruchio) propyl] - carbamic
Acid-1,1-dimethylethyl ester (1S) -1 ′-(((exo-2-hydroxy-endo-2-aminomethyl-7,7-in 5 ml of dried, degassed N, N-dimethylformamide) Dimethylbicyclo (2.2.1) hept-1-yl) methyl) sulfonyl) spiro (1H-indene-1,4′-piperidine)
B (600 mg, 1.39 mmol) in a stirred solution of B
oc-L-methionine (381 mg, 1.53 mmol) and benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (B
OP) 743 mg (1.68 mmol) was added at room temperature. The resulting reaction mixture was protected from moisture and the pH was adjusted to 8-9 with isopropylethylamine. After 1 hour all volatile constituents were removed under reduced pressure and the residue was dissolved in 250 ml of ethyl acetate. The solution was washed successively with 10% aqueous citric acid, 50% sodium bicarbonate solution and brine. The organic phase was dried (sodium sulfate) and concentrated. Chromatography of the crude reaction product on silica gel (1:
Elution with 1 ethyl acetate-hexanes) gave the title compound as an amorphous solid: mp 82-92 ° C. HPLC: purity of not less than 92% at 214 nM NMR: existence of a solvent was confirmed in agreement with structure FAB MS: 670 (M ⁺ + thioglycerol) Elemental analysis C ₃₄ H ₅₁ N ₃ O ₆ S ₂ · 0.5 CHCl ₃ Calculated value: C, 57.42; H, 7.19; N, 5.82 Measured value: C, 57.58; H, 7.50; N, 5.83

Example 28

[Chemical 71] 2-amino-N-[[exo-2-hydroxy-7,7
-Dimethyl-1-[(spiro [1H-indene-1,
4'-piperidine] -1'-ylsulfonyl) methyl]
Bicyclo] 2.2.1] hept-2-yl] methyl]-
A continuous stream of 4-methylthio) -butanamide dry HCI gas was bubbled into an ice-cold solution of ethyl acetate (2 ml) containing 20 mg of the product of Example 27 for 5 minutes. After 30 minutes at 0 ° C., the reaction mixture was concentrated and the residue was washed with 2
Chromatography (chloroform-methanol-ammonium hydroxide, 93: 7: 0.7 v / v elution) on a piece of 0.25 mm precoated silica gel plate. Solid title compound (10.7 mg): mp 78-80 ° C.
Got as. _{TLC: Rf = 0.28 (CHCl 3} -CH 3 OH -NH 4 OH, 9
5: 5: 0.5) NMR: Consistent with structure and confirmed presence of solvent FAM MS: 562 (M ⁺ + H) Elemental analysis C ₂₉ H ₄₃ N ₃ O ₄ S ₂ · 0.75CHCl ₃ : Calculated value: C, 54.86; H, 6.77; N, 6.45 Found: C, 54.52; H, 6.90; N, 6.32.

Example 29

[Chemical 72] 5- (1,3 (2H) -dioxo-1H-isoindol-2-yl) -N-[[2-hydroxy-7,7-dimethyl-1-[(spiro [1H-indene-1,4 ′ −
Piperidine] -1'-ylsulfonyl) methyl] bicyclo [2.2.1] hept-2-yl] -methyl] dihydro-4-oxo-2H-1,3-thiazin- 3 (4H)
-Acetamide dried, degassed N, N-dimethylformamide 1.5 ml
(1S) -1 '-(((exo-2-hydroxy-
2-aminomethyl-7,7-dimethylbicyclo (2.
2.1) Hept-1-yl) -sulfonyl) spiro (1
H-indene-1,4'-piperidine) (67 mg, 0.
16 mmol) to a stirred solution of 4-oxo-5-phthalyl-1,3-thiazine-acetic acid (62 mg, 0.192
Mmol) and benzotriazol-1-yloxytris (dimethylamino) -phosphonium hexafluorophosphate (BOP) 88 mg (0.20 mmol) were added at room temperature. The reaction mixture formed was protected from moisture and the pH value was adjusted to 8-9 with diisopropylethylamine. After 24 hours all volatile constituents were removed under reduced pressure and the residue was suspended in 5 ml of toluene. The suspension is concentrated to give a crude product which is chromatographed on silica gel (96: 4: 0.4 CHCl ₃ —CH ₃ OH —NH ₄ OH).
) To the title compound (109 mg): mp 134-
137 ° C was obtained. NMR: Consistent with structure, confirmed presence of solvent; HPLC: 214 nM, purity of 94% or higher; FAB MS: 733 (M ⁺ + H) Elemental analysis C ₃₈ H ₄₄ N ₄ O ₇ S ₂ · 1.1CHCl ₃ : Calculation Value: C, 54.34; H, 5.26; N, 6.48 Found: C, 54.12; H, 5.22; N, 6.42

Example 30

[Chemical formula 73] 5-amino-N-[[1-[[spiro [1H-indene-1,4'-piperidin] -1-yl) -sulfonyl]
Methyl] -exo-2-hydroxy-7,7-dimethylbicyclo- [2.2.1] hept-2-yl] methyl]
Dihydro-4-o Kiso-2H-1,3-thiazine -3
(4H) -Acetamide The product of Example 29 (60 mg) was dissolved in 3 ml of methanol and treated with 50 ml of 95% hydrazine (1.59 mmol) at 23 ° C. After 24 hours the solvent was removed in vacuo and the residue suspended in toluene. This suspension was rotary evaporated to give a crude product which was
Chromatography (chloroform-methanol-ammonium hydroxide, 92: 8: 0.8 v / v elution) on a sheet of 0.5 mm precoated silica gel. The title compound was an amorphous solid (27 mg): mp 103-10.
Obtained as 6 ° C. NMR: Consistent with structure and confirmed presence of solvent HPLC: Purity 97% or more at 214 nM FAB MS: 605 (M ⁺ + H) Elemental analysis C ₃₀ H ₄₄ N ₄ O ₅ S ₂ · 0.6CHCl ₃ : Calculated value: C, 54.33; H, 6.64; N, 8.28 Found: C, 54.12; H, 6.60; N, 8.20.

Example 31

[Chemical 74] 1 '-[(5-oxospiro [bicyclo [2.2.1]]
Heptane-7,1'-cyclopropane] -2-yl) sulfonyl] -spiro [1H-indan-1,4'-piperidine] Spiro (1H-indan-1,4'-piperidine) hydrochloride (3 g, 13 0.5 mmol) was dissolved in 30 ml of methylene chloride. The resulting solution was cooled to 0 ° C and 3.76 ml.
Of triethylamine. Subsequently, chloroethylsulfonyl chloride (1.57 ml, 15 mmol) was added dropwise. The reaction mixture was warmed to room temperature over 1 hour and filtered. The filtrate was washed with water, sodium hydrogen carbonate solution and brine. The dried organic washes were concentrated and the residue was subjected to column chromatography on silica gel (elution with 98: 2 methylene chloride-ether) to give 1'-
(Vinylsulfonyl) spiro (1H-indane-1,
1.88 g of 4'-piperidine) was obtained. (Mp114-
115 ° C). 1 '-(Vinylsulfonyl) spiro (1H
-Indan-1,4'-piperidine) (185 mg, 0.
67 mmol) was combined with spiroheptadiene (5.1 g, 55 mmol) in 4 ml of benzene and heated to reflux for 48 hours. The solvent and excess reagents were removed under reduced pressure and the resulting residual oil was chromatographed on silica gel (4: 1).
Hexane-ethyl acetate elution) to obtain 216 mg of a solid substance, which was recrystallized from methanol to give a white needle substance (mp 176-177 ° C.). This substance 110.7mg
Was dissolved in 5 ml of dry THF under nitrogen atmosphere. The solution was cooled to 0 ° C. and treated with 0.1 ml borane-THF complex. After stirring for 1 hour, 0.1 ml of borane-THF complex was added to the reaction mixture and stirred for another hour at room temperature. The reaction mixture was recooled to 0 ° C. and the reaction was stopped by dropping water.
10 minutes later, 0.3 ml of 3N sodium hydroxide solution and 3
0.3 ml of 0% hydrogen peroxide solution was added. The resulting mixture was heated to 50 ° C. for 1 hour and left at 23 ° C. overnight. The reaction mixture was separated into ethyl acetate and brine. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were dried (MgSO
₄ ) Concentrated. Preparation of crude reaction product on silica gel TL
Purified by C (2: 1 hexane-ethyl acetate) to 2
The ingredients are obtained. Highly polar product (mp232-233
℃, from methanol) (0.15 mmol) was dissolved in 5 ml of methylene chloride and pyridinium chloride (2 mmo)
l) was used to oxidize at 23 ° C. The reaction mixture was filtered through Celite and the filtrate was applied to a 0.25 mm precoated silica gel plate. Elution with 2: 1 hexane-ethyl acetate and recrystallization from methanol gave the title compound as a white solid. mp210-212 ° C NMR: Consistent with structure, presence of solvent was confirmed. HPLC: Purity of 96% or more at 214 nM FAB MS: 386 (M ⁺ + H) C ₂₂ H ₂₇ NO ₃ S.0.3CH ₂ O Elemental analysis calculated: C, 67.59; H, 7.12; N , 3.58 Found: C, 67.66; H, 7.22; N, 3.53.

Example 32

[Chemical 75] 1 '-[(9,10-dihydro-9,10-ethanoanthracen-1] -yl) sulfonyl] -spiro [1H-
Indane-1,4'-piperidine] 1 '-(vinylsulfonyl) spiro (1H-indan-
1,4'-piperidine) (152 mg) in toluene 15 ml
It was combined with 350 mg of anthracene in the mixture and heated under reflux for 8 days. The solvent and excess reagent were removed under reduced pressure and the residual oil was chromatographed on silica gel (eluting with 4: 1 hexane-ethyl acetate) to give the title compound as an amorphous solid. NMR: Consistent with structure confirmed presence of solvent. HPLC: purity of 99% or more at 214 nM FAB MS: 456 (M ⁺ + H) C ₂₉ H ₂₉ NO ₂ S 0.05CH ₂ O.0.25HCl ₃ Elemental analysis calculated: C, 72.23; H, 6 0.08; N, 2.88 Found: C, 72.23; H, 5.92; N, 2.67.

Example 33

[Chemical 76] 1 '-(Spiro [bicyclo [2.2.1] hept-5-
Ene-7, l ' cyclopenta] 2-ylsulfonyl) - spiro [1H- indane-1,4' Piperi di
Down] 1 '- (vinylsulfonyl) spiro (1H-indan -
1,4'-piperidine) (100 mg) was combined with 500 mg spironononadiene in 3 ml toluene and heated to reflux for 17 hours. The solvent and excess reagent were removed under reduced pressure and the residual oil was chromatographed on silica gel (eluting with 4: 1 hexane-ethyl acetate) to give the title compound as an amorphous solid. mp115-119 ° C NMR: Consistent with structure, presence of solvent was confirmed. HPLC: purity of 99% or more at 214 nM FAB MS: 398 (M ⁺ + H) Elemental analysis for C ₂₄ H ₃₁ NO ₂ S.0.05CHCl ₃ Calculated value: C, 71.57; H, 7.76; N, 3.47 Found: C, 71.94; H, 7.81; N, 3.42.

Example 34

[Chemical 77] 1 '-(bicyclo [2.2.2] hept-5-ene-2
- ylsulfonyl) - scan pyro [1H- indan -1,
4'-piperidine] 1 '-(vinylsulfonyl) spiro (1H-indane-
1,4'-piperidine) (100 mg) in 10 ml of toluene
The resulting mixture was combined with 10 times the amount of cyclohexadiene and heated under reflux for 30 hours. Solvent and excess reagents were removed under reduced pressure,
Chromatography of the residual oil on silica gel (4:
1 Hexane-ethyl acetate elution) to give the title compound as an amorphous solid. mp 162-166 ° C NMR: Consistent with structure, presence of solvent was confirmed. HPLC: purity of 99% or more at 214 nM FAB MS: 358 (M ⁺ + H) Elemental analysis for C ₂₁ H ₂₇ NO ₂ S.0.1H ₂ O Calculated value: C, 70.19; H, 7.63; N , 3.90 Found: C, 70.30; H, 8.03; N, 3.61.

Example 35

[Chemical 78] 1 '-[[2'-[[(2-methoxyethoxy) methoxy] methyl] spiro] bicyclo [2.2.1] hepta
5-ene-7, l ' cyclopropane] -2-i le] scan
Rufonyl) -spiro [1H-indane-1,4'-pipet
Lysine] 1 ′-(vinylsulfonyl) spiro (1H-indan-
1,4'-piperidine) (2.45g) in toluene 8ml
Hydroxymethylspirocycloheptadiene 2.2 in
g and hydroquinone (3 mg) were combined, and the mixture was heated under reflux for 17 hours. The solvent and excess reagent were removed under reduced pressure and the residual oil was chromatographed on silica gel (eluting with 1: 2 hexane-ethyl acetate) to give 3 components. The least polar component of these products (80 mg) was dissolved in methylene chloride containing 78 mg diisopropylethylamine and treated with 49 mg 2-methoxyethoxymethyl chloride. The reaction mixture was protected from moisture and stirred at 23 ° C overnight. The reaction mixture is concentrated to 0.5% residual material.
mm precoated silica gel plates. Elution with 1: 1 hexane-ethyl acetate gave the title compound. NMR: Consistent with structure confirmed presence of solvent. HPLC:> 99% pure FAB at 214 nM MS:
488 (M ⁺ + H)

Example 36

[Chemical 79] (1S-)-2-[[[exo-2-hydroxy-7,
7-dimethyl-1-[(spiro [1H-indene-1,
4'-piperidine] -1'-ylsulfonyl) methyl]
Bicyclo [2.2.1] hept-2-yl] methyl] amino] -N- (2-methoxy-2-oxoethyl)-
N, N-dimethyl-2-oxo-ethaneaminium salt and trifluoroacetic acid (1: 1) (1S-)-1 '-(((exo-2-hydroxy-endo-2-aminomethyl-7,7 -Dimethylbicyclo (2.2.1) hept-1-yl) methyl) sulfonyl) spiro (1H-indene-1,4'-piperidine)
To a stirred solution of (108 mg, 0.25 mmol) in 5 ml of toluene was added 1 ml of toluene containing 0.5 mmol of methylimino-acetic anhydride. Tetrahydrofuran (2 ml) was added,
The cloudy liquid was stirred overnight at 23 ° C. The reaction mixture was filtered and concentrated. This residue was dissolved in 5 ml N, N-dimethylformamide and subsequently treated with methyl iodide (0.5 ml) and diisopropylethylamine (0.2 ml).
The resulting solution was protected from moisture and heated at 50 ° C. for 5 hours. Further, 0.5 ml of methyl iodide was added and heating was continued for 5 hours. The reaction mixture was concentrated and the residue was purified by reverse phase HP
Purified by LC (Vidac Protein and
Peptide C-18 column, mobile phase = water-0.1% trifluoroacetic acid (TFA) in acetonitrile). Fractions containing the title compound were combined and concentrated. The residue was dissolved in dioxane and the solution was lyophilized to give the TFA salt of the title compound as a white powder. NMR: Consistent with structure confirmed presence of solvent. HPLC: 99% or higher purity at 214 nM FAB MS: 588 (M ⁺ + H) C ₃₁ H ₄₆ N ₃ O ₆ S · 1.8CF ₃ CO ₂ H · 1.0 Elemental analysis for dioxane Calculated value: C, 52. 61; H, 6.27; N, 4.77 Found: C, 52.58; H, 6.40; N, 4.76.

Example 37

[Chemical 80] (1R-Syn) -1 ′-[[(3-bromo-1,7-dimethyl-2-oxobicyclo [2.2.1] hept-7
-Yl) methyl] sulfonyl] -spiro [1H- indene
1,4'-Piveridine] 15 ml of DCM contained (-)-3-bromocamphorsulfonic acid ammonium salt (100 mg, 0.304 mM, FW
= 328.23) was dissolved. 5 equivalents of thionyl chloride (FW = 118.97, d = 1.631, 1.52
mM, 120 ml) and the mixture was stirred under a nitrogen balloon.
The reaction was carried out at 0 ° C for 1 hour. After 1 hour, the mixture was concentrated to give 63.12 mg (0.191 mM) of crude acid chloride.
47.13 mg of indene HCl salt was dissolved in 20 ml of THF. Acid chloride was added along with 2 equivalents of DIEA and reacted at room temperature for 1 hour. Then concentrate and 1N HCl 2
x200ml, H ₂ O 2x200ml, washed with brine 2 x 200 ml, followed by concentration and then dried over sodium sulfate. 25
Flash chromatography was performed with% EtOAc / petroleum ether.

Example 38

[Chemical 81] Zinc dust (24 mg, 0.367 mmo) was added to a solution of the product of Example 37 (107 mg, 0.300 mmol) in glacial acetic acid (10 ml).
l) was added. The temperature was then raised to reflux. After 30 minutes, the mixture was cooled to room temperature, filtered and then concentrated under reduced pressure. Purification by flash chromatography (35% ethyl acetate in petroleum ether as eluent) gave 80 mg of product as a white amorphous foam. NMR (300 MHz, CDCl ₃ ): Consistent with structure. HPLC (Vidak C18 column, H ₂ O / CH ₃ CN gradient containing 0.1% TFA from 95/5 to 0/100, 1
5 min gradient, flow rate = 1.5 ml / min): purity: 98%, rt = 12.67 min FAB MS: 400.91 [M + 1] ⁺ C ₂₃ H ₂₉ NO ₃ Analysis Calculated for S: C, 69 .13; H, 7.32; N, 3.51 Found: C, 69.25; H, 7.30; N, 3.48.

Example 39

[Chemical formula 82] 1 '-[[(7,7dimethyl-2-oxobicyclo [2.2.1] hept-1-yl) -methyl] sulfonyl] -3'-phenyl-spiro [1H-indene-1 ,
4'-Piperidine] ethanolamine (6.66 ml, 0.1103 mmol) was placed in a 3-neck round bottom flask and heated to reflux. Once the reflux started, styrene oxide (6.28 ml,
0.0557 mmol) was added dropwise to the reaction mixture over 15 minutes. The reaction mixture was refluxed for another 2 hours and then cooled. The product, N- (2-hydroxyethyl) -N- (2-hydroxy-2-phenylethyl) amine, was obtained as a clear oil by vacuum distillation. N- (2
-Hydroxyethyl) -N- (2-hydroxy-2-phenylethyl) amine (1.30 g, 7.16 mmol) was dissolved in chloroform and thionyl chloride (1.05 ml, 14.32 mmol) was added to 10 under nitrogen atmosphere. It was added dropwise over minutes. The reaction mixture was then refluxed for 1 hour and cooled to room temperature. Water was added to the reaction mixture and stirred for 1 hour. The reaction mixture was separated and the organic layer was washed 3 times with 3N HCl. The aqueous layers were combined, made basic with 40% sodium hydroxide and then extracted 3 times with ether, and the organic layers were combined and dried over sodium sulfate. The organic layer was filtered and concentrated to give a yellow oil. The yellow oil dissolves in ether and di-t
-Butyl dicarbonate (1.50 g, 6.87 mmol)
And triethylamine (500 ml, 3.59 mmol) were added together. The mixture was stirred overnight, H ₂ O (2 times), 0.1
Wash with NH Cl (twice), sodium bicarbonate (twice).
The organic layer was dried over sodium sulfate, and the filtered solution was concentrated to give a yellow oil. Dissolve this oil in CH ₂ Cl ₂ ,
It was injected into a silica gel column. The column is 1: 1 CH ₂ Cl ₂ /
Elute with hexane. The product fractions were combined and concentrated to dryness to give the product N- (2-hydroxyethyl) -N- (2-hydroxy-2-phenylethyl) -t-butylcarbamate. Indene (268 ml, 2.30 mmol) was dissolved in dry THF (2 ml) and lithium bis (trimethylsilyl) amide (1M solution in THF, 4.6 ml, 4.60 mmol) was added over 10 min under nitrogen atmosphere on ice bath. added.
The mixture was stirred on the cooling bath for 30 minutes, which was then stirred on an ice bath of N- (2-hydroxyethyl)-.
To a solution of N- (2-hydroxy-2-phenylethyl) -t-butyl carbamate (694 mg, 2.30 mmol) was added over 10 minutes. Cool the mixture under nitrogen 2
After stirring for an hour, the mixture was stirred at 25 ° C. for 30 minutes and concentrated to give an orange oil. Hexane containing 10% ethyl acetate was added and the resulting mixture was poured onto a silica gel column packed with hexane containing 10% ethyl acetate. Elution was performed with the same solvent, and the product fractions were concentrated to yield 1 '-(t
-Butyloxycarbonyl) -spiro- (indene-
3'-phenyl-1,4'-piperidine) was obtained.
1 '-(t-butyloxycarbonyl) -spiro- (indene-3'-phenyl-1,4'-piperidine) (2
90.9 mg, 0.842 mmol) in ethyl acetate,
It was saturated with HCl gas for 30 minutes with stirring in an ice bath. The operation of concentrating the mixture to dryness and re-concentrating from ether was repeated 3 times to obtain spiro (1H-indene-3-phenyl-1,4'-piperidine) hydrochloride. Spiro (1H-indene-3-phenyl-1,4'-piperidine) hydrochloride (205.2 mg, 0.690 mmol) and (+)
-10-camphorsulfonyl chloride (196 mg,
0.782 mmol) in THF and the pH was adjusted to 9 with triethylamine (196 ml, 1.41 mmol). The reaction mixture was stirred at 25 ° C. overnight, concentrated to dryness, redissolved in CH ₂ Cl ₂ , poured onto a silica gel column and eluted with CH ₂ Cl ₂ . The product fractions were combined and evaporated to dryness to give the title compound,
It was crystallized from ether and dried under vacuum overnight. mp: 183 ° C.-215 ° C. NMR: Consistent with structure HPLC: Purity> 95% MS: M + H 476.3 (FAB) Elemental analysis C ₂₉ H ₃₃ NO ₃ S.0.50H ₂ O Calculated value C, 71.86 H, 7.07; N, 2.89 Found C, 71.88; H, 7.03; N, 2.87.

Example 40

[Chemical 83] 1 '- [[(7,7-dimethyl-2'-oxospiro [bicyclo [2.2.1] heptane-2,5'-oxazolidin] -1-yl) methyl] sulfonyl] - scan pyro
[1H-indene-1,4'-piperidine] (1S (1a, 2a, 4a))-2-hydroxy-7,
7-dimethyl-1-((spiro- (1H-indene,
1,4'-Piperidin) -1'-yl-sulfonyl) methyl) -bicyclo- (2.2.1) heptane-2-acetic acid (100 mg, 0.217 mmol), diphenylphosphoryl azide (51.5 ml, 0. 239 mmol), triethylamine (66.2 ml, 0.471 mmol) were combined in DHF. The mixture was stirred overnight and then dried. The residue is converted to CH ₂ Cl ₂
It was dissolved in CH ₂ Cl ₂ and injected into a silica gel column and eluted with CH ₂ Cl ₂ containing 5% methanol. The product fractions were combined and concentrated to dryness to give the title compound as a white solid from ether which was dried under vacuum overnight. NMR: Consistent with structure HPLC: Purity> 93% MS: M + H 457.3 (FAB) Elemental analysis C ₂₅ H ₃₂ N ₂ O ₄ S Calculated value C, 65.76; H, 7.06; N, 6.14 Found C, 65.76; H, 7.42; N, 5.80.

Example 41

[Chemical 84] (1S-exo)-[2-hydroxy-7,7-dimethyl-1-[(spiro [1H-indene-1,2′-piperidin) -1′-ylsulfonyl) methyl] bicyclo [2.2.1 ] Hept-2-yl] carbamic acid 1,1
- dimethylethyl an ester (1S) -1 '- [[(7,7-dimethyl-2-oxobicyclo [2.2.1] hept-1-yl) - methyl] sulfonyl] - spiro [1H- indene -1 , 4'-piperidine] (1.92 g, 4.81 mmol) was added to 2 ml of toluene with zinc iodide (47 mg, 0.15 mmol) and trimethylsilyl cyanide (960 ml, 7.21 mmol) was added to the mixture under a nitrogen atmosphere. ) Was added dropwise. The reaction mixture was cooled and then diluted with 10 ml dry THF. Lithium aluminum hydride (1M solution in THF, 8.6
ml, 8.6 mmol) was added dropwise over 5 minutes and the mixture was kept stirring at 25 ° C. for 2 hours. The reaction mixture was then diluted with ether (N50 ml) and 10% sodium hydroxide was added dropwise until no more gray precipitate appeared. The mixture was filtered and the filtrate washed with sodium bicarbonate and brine, the organic layer separated and dried over sodium sulfate. The organic layer was filtered, the filtrate was concentrated and the residue was dissolved in CH ₂ Cl ₂ .
This is put on a silica gel column and CH of 97/3 / 0.3
Elution with ₂ Cl ₂ / methanol / ammonium hydroxide collected the product fractions. The product fractions were combined and concentrated to dryness. The desired compound (1S) -1 '-[[(7,7
-Dimethyl- (2-endo-aminomethyl-2-exo-hydroxy) -bicyclo [2.2.1] hept-1-
Il) -methyl] sulfonyl] -spiro [1H-indene-1,4'-piperidine] was obtained as a white foam from ether. (1S) -1 '-[[(7,7-
Dimethyl- (2-endo-aminomethyl-2-exo-
(Hydroxy) -bicyclo [2.2.1] hept-1-yl) -methyl] sulfonyl] -spiro [1H-indene-1,4'-piperidine] (44.9 mg, 0.104 mm
ol) and di-t-butyl dicarbonate (25 mg, 0.1
15 mmol) was added together to 5 ml CH ₂ Cl ₂ . The reaction mixture was treated with triethylamine (18.1 ml, 0.13 mmol) and stirred at 25 ° C for 30 minutes. The reaction mixture was placed on a silica gel column and eluted with hexane containing 15% ethyl acetate. The product fractions were combined and concentrated to dryness. The title compound was obtained from CH ₂ Cl ₂ / hexanes as a white solid which was dried under vacuum overnight. mp: 71 ° C.-115 ° C. NMR: Consistent with structure HPLC: Purity> 95% Elemental analysis C ₂₉ H ₄₂ N ₂ O ₅ S. Calculated value of 0.45 C, 66.14; H, 8.73; N, 5.03 Found C, 66.21; H, 8.52; N, 4.75.

Example 42

[Chemical 85] (1S-exo) -3-Hydroxy-N-[[2-hydroxy-7,7-dimethyl-1-[(spiro [1H-indene-1,4'-piperidin) -1'-ylsulfonyl) methyl] Bicyclo [2.2.1] hept-2-yl] methyl] -2- (hydroxymethyl) -2-methyl
- propanamide (1S) -1 '- [[(7,7-dimethyl - (2-End - aminomethyl-2-exo - hydroxy) - bicyclo [2.2.1] hept-1-yl) - methyl ] Sulfonyl] -spiro [1H-indene-1,4′-piperidine] (51 mg, 0.118 mmol) and 2,2-bis (hydroxymethyl) -propionic acid (19 mg, 0.142)
mmol), 1-hydroxybenzotriazole hydrate (H
BT) (19 mg, 0.142 mmol), 1-ethyl-3-
(Dimethylaminopropyl) carbodiimide (a) HCl
(EDC) (27 mg, 0.142 mmol) in 5 ml DM
All added together in F. Then triethylamine (4
6 ml, 0.33 mmol) was added to adjust pH to 9, and the mixture was stirred overnight at 25 ° C. The reaction mixture was concentrated to dryness and treated with 5% citric acid solution. The aqueous layer was made basic with saturated sodium bicarbonate and then extracted 3 times with ethyl acetate. The organic layers were combined and dried over sodium sulfate. The organic layer was filtered, the filtrate was concentrated, and the obtained residue was dissolved in CH ₂ Cl ₂ .
Place this on a silica gel column and contain 3% methanol
Eluted in CH ₂ Cl ₂ . The product fractions were combined and concentrated to dryness.
The title compound was obtained as a white solid from CH ₂ Cl ₂ / hexane, which was dried under vacuum overnight. mp: 167 ° C.-170 ° C. NMR: Consistent with structure HPLC: Purity> 99% MS: M + H 547.3 (FAB) Elemental analysis Calculated value for C ₂₉ H ₄₂ N ₂ O ₆ S C, 63.71; H, 7 .74; N, 5.12 found C, 63.65; H, 7.59; N, 4.88.

Example 43

[Chemical 86] (1S-exo) -4-benzoyl-N-[[2-hydroxy-7,7-dimethyl-1-[(spiro [1H-indene-1,4'-piperidin) -1'-ylsulfonyl) methyl] bicyclo [2.2.1] hept-2-yl] methyl] - Ben Zuamido (1S) -1 '- [[(7,7-dimethyl - (2-end - aminomethyl-2-exo - hydroxy) - Bicyclo [2.2.1] hept-1-yl) -methyl] sulfonyl] -spiro [1H-indene-1,4'-piperidine] 49.6 mg (0.115 mmol), EDC 26.
5 mg (0.138 mmol) and 18.7 mg (0.1%) of HBT.
38 mmol), 48 ml of triethylamine (0.345 mm
ol), 31.3 mg of 4-benzoylbenzoic acid instead of 2,2-bis (hydroxymethyl) -propionic acid
The same operation as in Example 42 was performed except that (0.138 mmol) was used. Elution from the column was performed with CH ₂ Cl ₂ containing 2% methanol. The title compound obtained was dried under vacuum overnight. mp: 110 ° C.-135 ° C. NMR: Consistent with structure HPLC: Purity> 94% MS: M + H 639 (FAB) Elemental analysis C ₃₈ H ₄₂ N ₂ O ₅ S 0.40 C ₆ H ₁₄ Calculated value C, 72. 06; H, 7.13; N, 4.16 Found C, 72.01; H, 7.14; N, 4.18.

Example 44

[Chemical 87] S- [1S-exo)-[[2-hydroxy-7,7-
Dimethyl-1 [(Spiro [1H-indene-1,4'-
Piperidine] -1'-ylsulfonyl) methyl] bicyclo [2.2.1] hept-2-yl] methyl]]-3-
Benzoyloxy- 2- (t-Boc-amino) -pro
Panamido (1S) -1 ′-[[(7,7-dimethyl- (2-endo-aminomethyl-2-exo-hydroxy) -bicyclo [2.2.1] hept-1-yl) -methyl] sulfonyl ] -Spiro [1H-indene-1,4'-piperidine] 94.5 mg (0.22 mmol), EDC 49.8
mg (0.26 mmol), HBT 35.2 mg (0.26 mm)
ol), 90 ml of triethylamine (0.66 mmol),
76.8 mg of t-boc-L-serine (bzl) instead of 2,2-bis (hydroxymethyl) -propionic acid
The same operation as in Example 42 was performed except that (0.26 mmol) was used. Elution from column is 98/2 / 0.5 CH
Performed with ₂ Cl ₂ / methanol / ammonium hydroxide. The title compound obtained from ether was dried under vacuum overnight. mp: 75 ° C.-95 ° C. NMR: Consistent with structure HPLC: Purity> 98% MS: M + H 639 (FAB) Elemental analysis Calculated value for C ₃₉ H ₅₃ N ₃ O ₇ S C, 66.16; H, 7. 55; N, 5.94 Found C, 66.04; H, 7.68; N, 5.84.

Example 45

[Chemical 88] [1S- [1. α, 2. β, 2 (R *), 4. β]] −
2-Amino-N [[1-[[(2,3-dihydrospiro [1H-indan-1,4'-piperidin] -yl) sulfonyl] methyl] -2-hydroxy-7,7-dimethylbicyclo [2 ． 2.1] Hept-2-yl] methyl]
3-Hydroxy-propanamide 4% of the product of Example 44 (120 mg, 0.17 mmol)
It was dissolved in methanol containing formic acid. Palladium hydroxide catalyst (25 mg) was added to the solution and on a PARR apparatus,
Place in 50 p.si hydrogen overnight. The reaction mixture was filtered through solka floc and the filtrate was concentrated to a clear oil. This oil was dissolved in 2 ml of ethyl acetate and cooled to 0 ° C. At this point, the previously cooled saturated HCl / ethyl acetate solution was added dropwise. The reaction mixture was stirred for 1 hour and then concentrated to dryness. The residue obtained was partitioned between ethyl acetate and saturated sodium bicarbonate, extracted three times with ethyl acetate, the organic layers were combined and dried over sodium sulfate. The organic layer was filtered, the filtrate was concentrated and the resulting residue was CH ₂ Cl ₂
Dissolved in. Put this on a silica gel column, 95/5
/0.5 was eluted with CH ₂ Cl ₂ / methanol / ammonium hydroxide. The product fractions were combined and evaporated to dryness. The title compound was obtained from ether as a white solid, which was dried under vacuum overnight. mp: 70 ° C.-110 ° C. NMR: Consistent with structure HPLC: Purity> 93% MS: M + H 520.3 (FAB) Elemental analysis C ₂₇ H ₄₁ N ₃ O ₅ S 0.25C ₄ H ₁₀ calculated value C , 61.31; H, 8.20; N, 7.67 Found C, 61.35; H, 8.11; N, 7.58.

Example 46

[Chemical 89] 3-[[[[2-hydroxy-7,7-dimethyl-1-
[(Spiro [1H-indene-1,4'-piperidine]]
-1'-ylsulfonyl) methyl] bicyclo [2.2.
1] -hepty-2-yl] methyl] amino] carbonyl] bicyclo [2. 2.1] Hept-5-ene-2-ca
Rubonic acid (1S)-(((7,7-dimethyl- (2-endo-aminomethyl-2-exo-hydroxy) -bicyclo-
(2.2.1) -hepty-1-yl) -methyl) sulfonyl) spiro (1H-indene-1,4′-piperidine) 98.5 mg, 0.23 mmol) in 5 ml of THF bicyclo (2.2.1). ) -5-Heptene-2,3-dicarboxylic anhydride (43 mg, 0.26 mmol). Triethylamine (50 ml, 0.36 mmol) was added dropwise to the reaction solution to adjust the pH to 9. The reaction mixture was stirred overnight and then concentrated to dryness. The obtained residue was dissolved in CH ₂ Cl ₂ , poured into a silica gel column, and eluted with 97/3 / 0.3 chloroform / methanol / acetic acid. The product fractions were combined and concentrated to dryness. The title compound was obtained as a white solid from ether and dried in vacuo overnight. Melting point: 128-165 ° C NMR: Consistent with structural formula HPLC:> 95% pure MS: M + H 595 (FAB) C ₃₃ H ₄₂ N ₂ O ₆ S .0.10 CH ₂ Cl ₂ analysis; Calculated value: C, 64.74; H, 7.12; N, 4.56 Found: C, 64.76; H, 7.07; N, 4.66.

Example 47

[Chemical 90] (1S) -1 '-(((2-endo-cyanomethyl-
7,7-Dimethyl-exo-2-hydroxybicyclo-
(2.2.1) - hept-1-yl) methyl) sul Honi
Le) -spiro (1H-indene-1,4'-piperidi
Emissions) lithium bis (trimethylsilyl) amide (21.3 mL
Solution of 1.0 M in THF (21.3 mmol) under N ₂ -7
Cool to 8 ° C. and add acetonitrile (1.07 ml, 20.4
mmol) and stirred for 15 minutes. (1S) -1'-
(((7,7-Dimethyl-2-oxobicyclo (2.
2.1) -hepty-1-yl) methyl) sulfonyl) spiro (1H-indene-1,4′-piperidine) (40
THF solution (30 ml) of g, 10 mmol) was added dropwise, and after completion of the addition, the mixture was stirred for 10 minutes. 6N HCl (2.8 ml) was added to the cooled reaction all at once and the mixture was warmed to 25 ° C. The mixture was diluted with H ₂ O (25 ml) and washed with EtOAc (3 x 100
ml). The organic layers were combined, washed with H ₂ O (25 ml) and brine (25 ml), dried over Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo. Trituration with ether gave the title compound (4.1
7 mg, 93% yield, crystalline solid (mp 199-202)
° C). TLC: R _f = 0.69, silica GF (7% Et in CH ₂ Cl _2
2 O) NMR: Consistent with structural formula

(1S) -1 '-(((2-endo-aminoethyl-7,7-dimethyl-2-exo-hydroxybicyclo (2.2.1) -hepty-1-yl) methyl)
Sulfonyl) spiro (1H-indene-1,4'-piperid
(Lysine) under nitrogen, lithium aluminum hydride (1.0M T
HF solution (8.0 ml, 8.0 mmol) was cooled to 0 ° C,
(1S) -1 '-(((2-endo-cyanomethyl-
7,7-Dimethyl-2-hydroxybicyclo- (2.
2.1) -hepty-1-yl) methyl) sulfonyl) spiro (1H-indene-1,4′-piperidine) (4.
4 g, 10.0 ml) in THF (37 ml) was added dropwise and the reaction was stirred for 10 minutes. While stirring rapidly, the reaction solution was added with H ₂ O (0.37 ml) and 20% NaOH (aqueous).
(0.40 ml) and H ₂ O (1.46 ml), followed by
Extracted with EtOAc (3 x 150 ml). Combine the organic layers and add H ₂
Wash with O (25 ml) and brine (25 ml), dry over Na ₂ SO ₄ ,
Filter and concentrate in vacuo to dryness. Silica gel (90/1
The product fractions were obtained by flash chromatography with 0/1/1 CH ₂ Cl ₂ / MeOH / H ₂ O / HOAc), pooled and concentrated to dryness. The residue was treated with saturated Na ₂ SO ₃ (aq) and extracted with EtOAc (3 x 100 ml). The combined organic layers were washed with H ₂ O (25 ml) and brine (25 ml), dried over Na ₂ SO ₄ , filtered and concentrated to dryness to give the title compound (2.55
g, 57% yield) was obtained as a white foam / solid. TLC: R _f = 0.27 silica GF (90/10/1 /
CH ₂ Cl ₂ / MeOH / H ₂ O / HOAc) NMR of 1: Consistent with structural formula

[0109]

[Chemical Formula 91] (1S-exo) -N- [2- [2-hydroxy-7,
7-dimethyl-1- [spiro [1H-indene-1,
4'-piperidine] -1'-ylsulfonyl) methyl]
Bicyclo [2.2.1] hept-2-yl] ethyl]-
4- Yodobenzua bromide (1S) -1 '- (( (2- end - aminoethyl -
7,7-Dimethyl-2-exo-hydroxybicyclo-
(2.2.1) -hepty-1-yl) methyl) sulfonyl) spiro (1H-indene-1,4′-piperidine)
(60 mg, 0.135 mmol) was dissolved in _{CH 2 Cl 2 (1ml),} 4- iodo-benzoyl chloride (36.0 mg, 0.
(135 mmol) and Et ₃ N to adjust its pH to 9.5. The reaction solution was stirred for 30 minutes at 25 ° C., and silica gel (CH
Flash chromatograph with 8% Et ₂ O in ₂ Cl ₂ ,
The title compound (45 mg, 50% yield) was obtained as a white foam from Et ₂ O (mp 98-138 ° C, shrink). TLC: R _f = 0.35 silica GF (10% Et in CH ₂ Cl _2
2 O) NMR: Consistent with structural formula HPLC: 95.8% pure M. S. : (FAB) M + H + thioglycerol = 78
3 C ₃₂ H ₃₉ IN ₂ O ₄ S ・ 0.30 C ₄ H ₁₀ O; ・ Analysis for 0.35 H ₂ O; Calculated: C, 56.70; H, 6.12; N, 3.98 Measured value : C, 56.73; H, 6.11; N, 4.01

Example 48

[Chemical Formula 92] (1S-exo) -N- [2- [2-hydroxy-7,
7-dimethyl-1-[(spiro [1H-indene-1,
4'-piperidine] -1'-ylsulfonyl) methyl]
Bicyclo [2.2.1] hept-2-yl] ethyl]-
Following the procedure of cyclopropane mosquito Rubokisamido Example 47, but using cyclopropylcarbonyl chloride (12.4 ml, 0.135 mmol) in place of 4-iodo-benzoyl chloride, the title compound was prepared. Flash chromatography of the reaction mixture on silica gel (15% Et ₂ O in CH ₂ Cl ₂ ) gave the title compound (36.6 mg, 53% yield) from ether to white foam (mp 93-105 ° C, shrink +). Bubbles) TLC: R _f = 0.22 silica GF (5% Et in CH ₂ Cl _2
2 O) NMR: Consistent with structural formula HPLC: 96.8% M. S. : (FAB) M + H + thioglycerol = 62
Analysis for 1 C ₂₉ H ₄₀ N ₂ O ₄ S 0.20 C ₇ H ₁₀ O Calculated value: C, 67.84; H, 8.03; N, 5.31 Found: C, 67.69; H , 8.06; N, 5.06

Example 49

[Chemical formula 93] (1S-exo) -N- [2- [2-hydroxy-7,
7-dimethyl-1-[(spiro [1H-indene-1,
4'-piperidine] -1'-ylsulfonyl) methyl]
Bicyclo [2.2.1] hept-2-yl] ethyl]-
2,2-Dimethyl -propanamide Following the procedure of Example 47, but using trimethylacetyl chloride (16.6 ml, 0.135 mmol) in place of 4-iodobenzoyl chloride, the title compound was prepared. Flash chromatography of the reaction on silica gel (13% Et ₂ O in CH ₂ Cl ₂ ) yielded the title compound (32.8 mg, 46% yield) from Et ₂ O as a white foam (mp 78-104 ° C., shrink). + Foam). TLC: R _f = 0.29 silica GF (15% Et in CH ₂ Cl _2
2 O) NMR: Consistent with structural formula HPLC: 97.6% M. S. : (FAB) M + H + thioglycerol = 63
Analysis for 7 C ₃₀ H ₄₄ N ₂ O ₄ S 0.20 C ₄ H ₁₀ O 0.30 H ₂ O; Calculated: C, 67.38; H, 8.56; N, 5.10 Measured; C, 67.37; H, 8.52; N, 5.02

Example 50

[Chemical 94] (1S-exo) -N- [2- [2-hydroxy-7,
7-dimethyl-1-[(spiro [1H-indene-1,
4'-piperidine] -1'-ylsulfonyl) methyl]
Bicyclo [2.2.1] hept-2-yl] ethyl]-
4-nitro - Following the procedure of Ben Zuamido Example 47, except 4-nitrobenzoyl chloride (25.1 mg, 0.135 mmol) and using in place of 4-iodo-benzoyl chloride, the title compound was prepared. Flash chromatography of the reaction on silica gel (10% Et ₂ O in CH ₂ Cl ₂ ) yielded the title compound (41.6 mg, 52% yield) from ether to a white foam (mp 118-133 ° C., shrink +). Foam). TLC: R _f = 0.26 silica GF (10% Et in CH ₂ Cl _2
2 O) NMR: Consistent with structural formula HPLC: 97.1% M. S. : (FAB) M + H + thioglycerol = 70
Analysis for 2 C ₃₂ H ₃₉ N ₃ O ₆ S · 0.30 C ₄ H ₁₀ O · 0.20 H ₂ O; Calculated value: C, 64.35; H, 6.90; N, 6.78 Measured value : C, 64.32; H, 6.98; N, 6.63

Example 51

[Chemical 95] (1S-exo) -N- [2- [2-hydroxy-7,
7-dimethyl-1-[(spiro [1H-indene-1,
4'-piperidine] -1'-ylsulfonyl) methyl]
Bicyclo [2.2.1] hept-2-yl] ethyl]-
4-Methoxy - Following the procedure of base Nzuamido Example 47, except p- anisoyl chloride (18.3 ml, 0.135 mmol) using in place of 4-iodo-benzoyl chloride, the title compound was prepared. Flash chromatography of the reaction on silica gel (15% Et ₂ O in CH ₂ Cl ₂ ) gave the title compound (3
6 mg, 46% yield) as a white solid from Et ₂ O (mp 98-1
21 ° C., shrinkage). TLC: R _f = 0.26 Silica GF (15% Et in CH ₂ Cl _2
2 O) NMR: Consistent with structural formula HPLC: 95.5% M. S. : M + H + thioglycerol _{= 687 C 33 H 42 N 2} O 5 S · 0.25 C 4 H 10 O on the analysis: Calculated: C, 68.36; H, 7.51 ; N, 4.69 Found: C, 68.14; H, 7.67; N, 4.55

Example 52

[Chemical 96] (1S-exo) -1 '-[[[2- [2-
[[[(1,1-Dimethylethyl) amino] carbonyl] amino] ethyl] -2-hydroxy-7,7-dimethylbicyclo [2.2.1] hept-1-yl] methyl] sulfonyl] -spiro [ 1H -Inden-1,4 '
-Piperidine ] (1S) -1 '-[[[endo-aminoethyl-7,7
-Dimethyl-exo-hydroxybicyclo [2.2.
1] -hepty-1-yl] methyl] sulfonyl] spiro (1H-indene-1,4′-piperidine) (60 mg,
0.135 mmol) was dissolved in THF (2 ml), treated with t-butylisocyanate (15.4 ml, 0.135 mmol) and stirred for 30 minutes at 25 ° C. After removal of solvent in vacuo, the residue was flash chromatographed on silica gel (25% Et ₂ O in CH ₂ Cl ₂ ) to give the title compound (27.
9 mg, 38% yield) as a white solid from Et ₂ O (mp 97-1
19 ° C., shrinkage and foam). TLC: R _f = 0.21 Silica GF (20% Et in CH ₂ Cl _2
2 O) NMR: Consistent with structural formula HPLC: 95.1% M. S. : (FAB) M + H + thioglycerol = 65
Analysis for 2 C ₃₀ H ₄₅ N ₃ O ₄ S · 0.25 C ₄ H ₁₀ O · 0.30 H ₂ O; Calculated value: C, 65.58; H, 8.54; N, 7.40 Measured value C, 65.70; H, 8.74; N, 7.05;

Example 53

[Chemical 97] Endo (1S) -1 ′-(((2-amino-7,7-dimethylbicyclo [2.2.1] hept-1-yl) methyl) sulfonyl) -spiro (1H-indan-1,4 ′
- piperidine) (670mg, 1.66mmol) and N ^a -TE
rt-Butyloxycarbonyl-5,5-dimethyl-L-
Thiazolidine-4-carboxylic acid (500 mg, 1.91 mm
10 ml of dry N, N-dimethylformamide containing
932 mg (2.11 mmol) of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate was added to the stirred solution of. The pH of the reaction mixture was adjusted to 8.5 with diisopropylethylamine and the reaction mixture was stirred at 23 ° C overnight. The reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and this solution was followed by saturated sodium bicarbonate solution (3x
25 ml) and brine. The organic phase was dried (sodium sulfate) and concentrated to give a brown solid. This was purified by chromatography on silica gel (chloroform-methanol-concentrated ammonium hydroxide, 98: 2: 0.2 v / v) to give a white solid. This material was dissolved in 10 ml of chloroform. The solution was cooled in an ice bath and treated dropwise with a 5 ml solution of chloroform containing 2.2 equivalents of m-chloroperoxy-benzoic acid. After the addition was completed, the ice bath was removed and stirring was continued for 24 hours. Dilute the reaction mixture to 100 ml with chloroform and add 1M sodium hydroxide solution (2x
30 ml) and brine. The organic phase was dried (sodium sulfate) and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (eluting with chloroform-methanol-concentrated ammonium hydroxide, 98: 2: 0.2 v / v) to give the title compound. NMR: Consistent with structure and confirmed presence of solvent HPLC:> 94% pure at 214 nM FAB MS: 678 (M ⁺ + H) C ₃₄ H ₅₁ N ₃ O ₇ S ₂ .0.8CHCl ₃ Elemental analysis: Calculated: C, 54.04; H, 6.75; N, 5.43 Found: C, 54.11; H, 6.64; N, 5.48.

Example 54

[Chemical 98] Endo (1S) -1 ′-(((2-amino-7,7-dimethylbicyclo [2.2.1] hept-1-yl) methyl) sulfonyl) spiro (1H-indan-1,4′-
Piperidine (660 mg, 2.05 mmol) and (S)
-3-[(t-butyloxycarbonyl) amino] -2
-Oxo-1-pyrrolidine- (R) -2-methylcarboxysuccinic acid (826.5 mg, 2.05 mmol),
1-in dry methylene chloride (20 ml) at room temperature under nitrogen
Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (392 mg, 2.05 mmol)
And 1-hydroxybenzotriazole hydrate (275
mg, 2.05 mmol). PH of reaction mixture
Was adjusted to 8.5 with triethylamine and the resulting solution was stirred for 12 hours. The reaction mixture was treated with methylene chloride (150
ml) and the resulting solution was saturated sodium hydrogen carbonate solution (2 x 40 ml), 10% citric acid solution (2 x 40 m).
l) and brine, then dried (magnesium sulfate) and concentrated to give the crude product. Analytically pure material was obtained using preparative HPLC chromatography (Vydac C-18 column (4.5 x 150 mm, water-acetonitrile-1% trifluoroacetic acid 45 min gradient) containing product. The homogeneous fractions were combined and concentrated.The residue was dissolved in methylene chloride containing trifluoroacetic acid (50%) at room temperature.After 2 hours, the volatiles were removed under reduced pressure to give the target compound as a trifluoroacetic acid salt. NMR: Consistent with structural formula, confirm presence of solvent HPLC:> 97% pure (at 214 mm) FAB MS: 615 (M ⁺ + H) Elemental analysis: C ₃₄ H ₄₇ F ₃ N ₄ O ₈ S. Calculated for 0.3H ₂ O · 0.8TFA: C, 51.59; H, 5.88; N, 6.74 Found: C, 51.59; H, 5.89; N, 6.81.

Example 55

[Chemical 99] Endo- (1S) -1 '-(((2-amino-7,7-
Dimethylbicyclo [2.2.1] hept-1-yl) methyl) sulfonyl) spiro (1H-indan-1,4 ′
-Piperidine) (216 mg, 0.53 mmol) and N
-T-Butyloxycarbonyl-D, L- (3-thienyl) alanine (160 mg, 0.59 mmol) at room temperature under nitrogen 1-ethyl-3-in 6 ml of dry methylene chloride.
Combined with (3-dimethylaminopropyl) carbodiimide hydrochloride (113 mg, 0.59 mmol) and 1-hydroxybenzotriazole (79 mg, 0.59 mmol). The pH of the reaction mixture was adjusted to 9 with triethylamine. The resulting solution was stirred for 12 hours. t
-Butyloxycarbonyl-D, L- (3-thienyl)
An additional 20 mg of alanine and 11 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride were added, stirred and continued for another 6 hours while maintaining the pH of the solvent between 8 and 9. The reaction mixture was mixed with methylene chloride (15
0 ml) and the resulting solution was saturated sodium hydrogen carbonate solution (2 x 40 ml), 10% citric acid solution (2 x 40 ml).
ml) and brine, then dried (magnesium sulfate) and concentrated to give the crude product. Analytically pure material was obtained using flash column chromatography on silica gel (chloroform-methanol-concentrated ammonium hydroxide eluent, 95: 5: 0.5 v / v). NMR: Consistent with structural formula, confirm presence of solvent HPLC:> 99% pure (214 nm) FAB MS: 656 (M ⁺ + H) Elemental analysis: C ₃₅ H ₄₉ N ₃ O ₅ S ₂ · 0.5H ₂ O Calculated for: C, 63.22; H, 7.58; N, 6.32 Found: C, 63.26; H, 7.54; N, 6.10

Example 56

[Chemical 100] Endo (1S) -1 ′-(((2-amino-7,7-dimethylbicyclo [2,2,1] hept-1-yl) methyl) sulfonyl) spiro (1H-indan-1,4′-
Piperidine) (67 mg, 0.156 mmol) and N-
Ethylcarboxymethyl-5,5-dimethyl-L-thiazolidine-4-carboxylic acid (57 mg, 0.23 mmol) was added to 1-ethyl-3- (3-dimethylaminopropyl) in 5 ml of dry methylene chloride at room temperature under nitrogen. ) Carbodiimide hydrochloride (44 mg, 0.23 mmol) and 1-hydroxybenzotriazole hydrate (31 mg,
0.23 mmol). The pH of the reaction mixture was adjusted to 8.5 with triethylamine and the resulting solution was stirred for 3 hours. The reaction mixture was diluted with methylene chloride (50 ml) and the resulting solution was washed with saturated sodium hydrogen carbonate solution (2 x 40 ml), 10% citric acid solution (2 x 40 ml) and brine then dried (sulfuric acid. Magnesium) and concentrated to give the crude product. Prepare analytically pure material thin layer chromatography (2 x 20 x 20 mm,
Precoated SiO ₂ plates, hexane - ethyl acetate eluent, 2: 1v / v) were obtained using a. The analytical product was isolated as a solid in homogeneous form. NMR: Consistent with structure confirmed presence of solvent. FAB MS: 660 (M ⁺ + H) Elemental analysis, calculated for C ₃₄ H ₄₇ N ₃ O ₆ S ₂ · 0.85H ₂ O · 0.1EtOAC: C, 60.40; H, 7.59; N, 6.14 Found: C, 60.37; H, 7.36; N, 6.13.

Example 57

[Chemical 101] Endo (1S) -1 ′-(((2-amino-7,7-dimethylbicyclo [2.2.1] hept-1-yl) methyl) sulfonyl) spiro (1H-indan-1,4′-
Piperidine) (4.0 g, 9.9 mmol) and Nα-
Dry N, N-containing t-butyloxycarbonyl-L-methionine sulfone (2.84 g, 11.9 mmol).
To a stirred solution of 50 ml of dimethylformamide, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate 5.65 g (1
2.87 mmol) was added. The pH of the reaction mixture was adjusted to 8.5 with diisopropylethylamine and the reaction mixture was stirred at 23 ° C. for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a solid. Dissolve this material in ethyl acetate,
Add this solution to saturated sodium bicarbonate solution (3 x 25 m
l) Washed successively with 10% citric acid solution (3 x 25 ml) and brine. The organic phase is dried (sodium sulfate) and concentrated to give 2-t-butyloxycarbonylamino-N- [1
-[[(2,3-Dihydrospiro [1H-indene-
1,4'-Piperidin] -1'-yl) sulfonyl] methyl] -7,7-dimethylbicyclo [2.2.1] hept-2-yl] -4- (methylsulfonyl) -butanamide is obtained, which Was purified by chromatography on silica gel (chloroform-methanol-concentrated ammonium hydroxide eluent, 95: 5: 0.5 v / v) to give a solid. This material was dissolved in 50 ml of ethyl acetate and the resulting solution was cooled to 0 ° C. and treated with a continuous stream of hydrogen chloride gas for 15 minutes. The ice bath was removed, the reaction vessel was sealed and stirring was continued at room temperature for another 45 minutes. The solvent and excess hydrogen chloride were removed under reduced pressure to give 2-amino-N- [1-[[(2,3-dihydrospiro [1H-indene-1,4'-piperidin] -1'-yl) sulfonyl. ] Methyl] -7,7-dimethylbicyclo [2.2.1] hept-2-yl] -4
-(Methylsulfonyl) -butanamide hydrochloride was obtained as an off-white solid (6.5g).

[Chemical 102] 2-Amino-N- [1-[[(2,3-dihydrospiro [1H-indene-1,4'-piperidin] -1'-yl) sulfonyl] methyl] -7,7-dimethylbicyclo [2. 2.1] Hept-2-yl] -4- (methylsulfonyl) -butanamide hydrochloride was chromatographed on silica gel (chloroform-methanol-concentrated ammonium hydroxide eluent, 90: 10: 1v).
/ V), a white solid was obtained, which was dissolved in 15 ml of methanol containing 1% acetic acid. To the reaction mixture was added 3 ml of aqueous formaldehyde and 1.5 of sodium cyanoborohydride.
6 g (24.8 mmol) was added. The resulting reaction mixture was stirred overnight at room temperature. The reaction mixture is concentrated under vacuum,
The residue was partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution. The phases were separated, the organic phase was washed with brine, dried (sodium sulfate) and concentrated under reduced pressure. Chromatography of the crude product on silica gel (chloroform-
Methanol-concentrated ammonium hydroxide eluent, 95: 5:
0.5 v / v) and purified by 2-dimethylamino-N
-[1-[[(spiro [1H-indan-1,4'-piperidin] -1'-yl) sulfonyl] methyl] -7,
7-Dimethylbicyclo [2.2.1] hept-2-yl] -4- (methylsulfonyl) -butanamide was obtained. NMR: Consistent with structure, confirmed presence of solvent; HPLC:> 98% pure (214 nM); FAB MS: 594 (M ⁺ + H); Elemental analysis C ₃₀ H ₄₇ N ₃ O ₅ S ₂ .0.1CHCl. Calculated for ₃ : C, 59.67; H, 7.84; N, 6.94 Found: C, 59.90; H, 7.24; N, 6.93.

Example 58

[Chemical 103] Dry degassed in 10 ml of N, N-dimethylformamide (1
S) -1 '-(((2-exohydroxy-2-endo-aminomethyl-7,7-dimethylbicyclo [2.2.
1] Hept-1-yl) methyl) sulfonyl) spiro (1H-indene-1,4′-piperidine) (300 m
g, 0.694 mmol) at room temperature into a stirred solution of Nt-
Butyloxycarbonyl-S-methyl-L-cystine (212 mg, 0.832 mmol) and benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) (398)
mg, 0.902 mmol) was added. The resulting reaction mixture was protected from moisture and the pH was adjusted to 8-9 with diisopropylethylamine. After 24 hours all volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and sodium hydrogen carbonate solution. The phases were separated and the organic phase was washed with saturated sodium hydrogen carbonate solution (3 x 40 ml) and brine then dried (magnesium sulphate) and concentrated. The crude product is chromatographed on silica gel (hexane-
Ethyl acetate eluent, 3: 1 V / V), the target compound was obtained. NMR: Consistent with structure, confirmed presence of solvent; HPLC:> 98% pure (214 nM); FAB MS: 650 (M ⁺ + H); Elemental analysis Calculated for C ₃₃ H ₅₀ N ₃ O ₆ S ₂ : C, 61.07; H, 7.71; N, 6.47 Found: C, 61.24; H, 7.98; N, 6.13.

Example 59

[Chemical 104] Dry degassed in 7 ml of N, N-dimethylformamide (1S)
-1 '-(((2-exo-hydroxy-2-endo-
Aminomethyl-7,7-dimethylbicyclo [2.2.
1] hept-1-yl) methyl) sulfonyl) spiro (1H-indene-1,4′-piperidine) (125 m
g, 0.311 mmol) to a stirred solution of S-hydantoin acetic acid (59 mg, 0.372 mmol) and benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BO
P) (178 mg, 0.404 mmol) was added. The resulting reaction mixture was protected from moisture and the pH was adjusted to 8-9 with diisopropylethylamine. After 24 hours, all volatiles were removed under reduced pressure and the residue was washed with ethyl acetate (100m).
It was partitioned between l) and sodium hydrogen carbonate solution. The phases were separated and the organic phase was saturated sodium hydrogen carbonate solution (3 x 40 ml).
And brine, then dried (magnesium sulfate) and concentrated. The crude product was first subjected to flash chromatography on silica gel (chloroform-methanol eluent, 96: 4 v / v) to give semi-purified material,
It was subjected to preparative thick layer chromatography on silica gel (chloroform-methanol-concentrated ammonium hydroxide eluent, 96: 4: 0.4 v / v) and triturated with ether-petroleum ether to give a white solid. The compound was obtained. NMR: Structure and match to confirm the presence of a ^{solvent; FAB MS: 543 (M +} + H); Elemental Analysis C ₂₈ H calcd for _{48 N 4 O 5 S: C} , 61.96; H, 7.00 N, 10.32. Found: C, 61.70; H, 7.36; N, 10.09.

Example 60

[Chemical 105] (1S) -1 ′-(((7,7-Dimethyl- (2-endoamino) -bicyclo [2.2.1] -hept-1-yl) -methyl) sulfonyl) spiro (1H-indene-
1,4'-piperidine) (3.47 mmol) and 4-
Nitrophenyl chloroformate (3.64 mmol)
Was combined in THF. The reaction mixture was treated with triethylamine (4.54 mmol) and stirred for 3 hours. The reaction mixture was concentrated to dryness and the resulting residue was purified by silica gel column eluting with 1% ethyl acetate in methylene chloride. The product fractions were combined and concentrated to dryness under vacuum. (1S) -1 '-(((7,7-dimethyl-
(4-Nitrophenyloxycarbonyl-2-endoamino) -bicyclo [2.2.1] -hept-1-yl)
-Methyl) -sulfonyl) spiro (1H-indene-
1,4'-piperidine was obtained from ether as a white solid. (1S) -1 '-(((7,7-Dimethyl-2-endo- (4-nitrophenyloxycarbonylamino) -bicyclo- [2.2.1] -hept-1-yl) -methyl) sulfonyl ) Spiro (1H-indene-1,4'-
Piperidine) (0.278 mmol) and (benzyloxycarbonyl) piperazic acid
(0.334 mmol) was combined in DMF. The reaction mixture was treated with triethylamine (0.401 mmol) and stirred for 2 hours. The reaction mixture was concentrated to dryness and the resulting residue was dissolved in CH ₂ Cl ₂ . The solution was placed on a silica gel column, elution was carried out in CH ₂ Cl ₂ 5% methanol, followed by CH ₂ Cl ₂ / methanol / acetic acid, 96/4 / 0.4. The product fractions were combined and evaporated to dryness. The target compound was obtained from ether as a white solid and dried under vacuum overnight. m. p. : 90 to 120 ° C. NMR: Consistent with structure HPLC:> 98% pure ^{MS: M -> H + =} 693.6 CHN: C 37 H 48 N 4 O 7 S · 0.20 mole C ₄ H ₁₀ O · 0.
Calcd for 25 mol H ₂ O C, 63.74; H, 7.15; N, 7.87 Found: C, 63.78; H, 7.08; N, 7.81.

Example 61

[Chemical formula 106] (1S) -1 '-(((7,7-Dimethyl-2-endo- (4-nitrophenyloxycarbonylamino) -bicyclo- [2.2.1] -hept-1-yl) methyl)
Sulfonyl) spiro (1H-indane-1,4'-piperidine) (0.193 mmol), triethylamine (0.29 mmol) and 3- (t-butoxycarbonylaminomethyl) piperidine (0.212 mmol).
The procedure of Example 60 second paragraph was carried out (instead of (benzyloxycarbonyl) piperazine acid). Chromatographic elution was 5% in CH ₂ Cl _2.
With ether in CH ₂ Cl ₂ 10% ether then CH ₂ Cl ₂
Performed with 1% methanol in medium. The desired compound was obtained from ether and dried under vacuum overnight. m. p. : 95 to 105 ° C. NMR: Consistent with structure HPLC:> 97% pure ^{MS: M + H + = 643.4} CHN: C 35 H 54 N 4 O 5 Calculated C for S · 0.20H ₂ O, 65.02; H, 8.48; N, 8.67 Found: C, 64.98; H, 8.43; N, 8.86.

Example 62 End- (1S) -1 '-(((2- (L-4 (t-
Toxycarbonylamino) glutaramyl) amino-
7,7-Dimethylbicyclo [2.2.1] hept-1-
Il) -methyl) -sulfonyl) spiro- (1H) -i
Andan-1,4 'piperidine

[Chemical formula 107] Endo- (1S)-in dimethylformamide (1 ml)
1 '-(((2-amino-7,7-dimethylbicyclo [2.2.1] hept-1-yl) -methyl) -sulfonyl) spiro- (1H) -indan-1,4'-piperidine ( 50 mg, 0.125 mmol), L-4 (t-butoxycarbonyl) glutaramic acid
(34 mg, 0.14 mmol), 1-ethyl-3- (3
Dimethylaminopropyl) carbodiimide hydrochloride (30 mg, 0.15 mmol) and 1-hydroxybenztriazole hydrate (20 mg, 0.15 mmol) were dissolved in an oven dry flask (50 ml) under nitrogen. Triethylamine (50 μl) was added to separate a white solid. After stirring for 1 hour, the solvent was removed under reduced pressure. The residue was dissolved in ether: methylene chloride (3: 1). The opaque solution was washed with sodium hydrogen carbonate (saturated, aqueous), water, potassium hydrogen sulfate (10%, aqueous) and brine. After drying over sodium sulfate, the organic material was filtered and concentrated. Methylene chloride: methanol (9:
The product was obtained by silica flash chromatography using 1), the solvent was evaporated and isolated as an oil. Hexane: ether was added and removed under reduced pressure to yield the title compound as a white foam. HPLC:> 99% MS: M + H ⁺ = 631.3 NMR: Consistent with structure Calculated for C ₃₃ H ₅₀ N ₄ O ₆ S .0.5DMF 0.5H ₂ O Calculated: C, 61.26; H , 8.12; N, 9.32 Found: C, 61.27; H, 8.05; N, 9.31.

Example 63 End- (1S) -1 '-(((2- (4 (imidazole
Ru-2-ethylacetyl) amino-7,7-dimethylbi
Cyclo [2.2.1] hept-1-yl) -methyl) su
Pyro (1H) -indan- (1,4 ′) piperidine hydr
Lochloride

[Chemical 108] Step 1: End- (1S) -1 '-(((2-4 (3-
Methyl-benzyloxy) imidazole) 2 (Echirua
Cetyl) amino-7,7-dimethylbicyclo- [2.
2.1] hept-1-yl) - methyl) - a sulfonyl)
Spiro (1H) -indan (1,4 ')-piperidine Under nitrogen, dimethylformamide (4 ml) was placed in a dry flask (50 ml). End (1S) -1'-
((2-Amino-7,7-dimethylbicyclo [2.2.
1] Hept-1-yl) -methyl) sulfonyl) spiro (1H) -indan- (1,4 ′)-piperidine (30
0 mg, 0.74 mmol), 4 (3-methylbenzyloxy) imidazole-2-ethylacetic acid (219 mg, 0.
8 mmol), 1-ethyl-3-methyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (1
53 mg, 0.8 mmol) and 1-hydroxybenztriazole hydrate (108 mg, 0.83 mmol)
Was added and the mixture was stirred until dissolution was complete. Triethylamine (400 μl) was added to make the solution basic (pH 9) and the solid separated. After stirring overnight at room temperature, the solvent was removed under reduced pressure. The resulting gum was methylene chloride:
Dissolved in ether (1: 3), the opaque solution was extracted with sodium hydrogen carbonate (saturated, aqueous) and brine. After drying the organic phase over sodium sulfate, the solution was filtered and concentrated. The product was purified by silica gel flash chromatography using methylene chloride: methanol: ammonium hydroxide (9: 1: 1) as solvent. The product fractions were concentrated to give the title compound as a white foam. HPLC:> 95% (42% + 53%) MS: M + H ⁺ = 659.3 NMR (CDCl ₃ ): Consistent with structure Analytical calculation for C ₃₈ H ₅₀ N ₄ O ₄ S .0.65H ₂ O: C , 68.05; H, 7.71; N, 8.36 Found: C, 68.03; H, 7.87; N, 8.60 Absolute ethanol (20 ml) -acetic acid (5 ml) in endo (1
S) -1 '-(((2-4- (3-methylbenzyloxyimidazole) -2-ethylacetylamino) -7,
Nitrogen was added to a solution of 7-dimethylbicyclo [2.2.1] hept-1-yl) -methyl) -sulfonyl) spiro- (1H) -indan- (1,4 ') piperidine (50 mg, 0.076 mmol). Bubbled. 5 minutes later, 10% P
d / C (50 mg) was added and the mixture hydrogenated overnight at 55 psi. The catalyst was removed by filtration and the solvent was concentrated to dryness under reduced pressure. Using the residue as a solvent, methylene chloride, methanol,
Purified by silica gel flash chromatography with ammonium hydroxide (9: 1: 1). The product fractions were collected and concentrated. The gum was redissolved in methylene chloride and filtered through a glass strainer. After concentrating the solution, the residue was dissolved in ethyl acetate (5 ml). The solution was cooled to 0 ° C. and saturated with hydrogen chloride gas (5 minutes bubbling). The solvent was removed under reduced pressure, ether was added and removed to give the title compound as a white solid. HPLC:> 90% (42% + 45%) MS: M + H + = 539.2 ( free base) NMR (CDCl _3): Consistent with structure _{C 30 H 42 N 4 O 3} S · HCl · 0.25 ether · 130H Analysis for ₂ O Calculated: C, 60.33; H, 7.86; N, 9.08 Found: C, 60.33; H, 7.48; N, 9.04.

Example 64

[Chemical 109] The product of Example A in DMF (10 ml) (500 mg, 1.
24 mmol) to a stirred solution of 2- (1-benzyloxymethylimidazol-5-yl) -4-methylsulfonylbutanoic acid HCl salt (506 mg, 1.30 mmol), DI
EA (0.70 ml, 4.0 mmol) and BOP (600
mg, 1.35 mmol) was added. After stirring for 14 hours at ambient temperature, the solvent was removed under reduced pressure. The residue was washed with EtOAc (75
ml) and washed with aqueous NaHCO ₃ (3 × 50 ml). The organic phase was dried (MgSO _4), filtered and the solvent was removed under reduced pressure. The benzyloxymethyl protecting group was replaced with EtOH-HOAc.
The residue was dissolved in a 4: 1 solution of (10 ml) and removed by hydrogenation over palladium black (75 mg) under 1 atmosphere of hydrogen for 24 hours. The catalyst was removed by filtration through Celite and the filtrate solvent was removed under reduced pressure. Volume mixing ratio residue as eluent 50: 50: 7 CHCl ₃ of, EtOAc, and was purified by pressurized silica gel column chromatography using _4% NH 4 OH-MeOH. Two diastereomers were obtained, each lyophilized from water containing 1% THF. The target compound is an isomer with a low Rf value. High Rf value isomer: Analysis: (C ₃₁ H ₄₄ N ₄ O ₅ S ₂ ) .1.0TFA1.1H ₂ O Calculated value: C, 52.45; H, 6.24; N, 7.37 Found: C, 52.69; H, 6.12 ; N, 7.32 TLC: Rf0.33 (50: 50: 7 CHCl 3: EtOA
c: 4% NH ₄ OH-MeOH) HPLC (method A): retention time 8.96 minutes FAB MS: m / z 617 (M ⁺ + H) ¹ H NMR (300 MHz, CDCl ₃ ): free base: d
7.70 (s.1H), 7.55 (br d, 1H),
7.15-7.25 (m, 4H), 7.00 (s.1)
H), 4.35 (m, 1H), 2.90 (s, 3H),
1.00 (s, 3H), 0.98 (s.3H) low Rf value isomer: _{Analysis: (C 31 H 44 N 4} O 5 S 2) · 1.0TFA · 1.3H 2 O Calculated: C, 52.55; H, 6.36; N, 7.43 Found: C, 52.89; H, 6.13 ; N, 7.43 TLC: Rf0.28 (50: 50: 7 CHCl 3 : EtOA
c: 4% NH ₄ OH-MeOH) HPLC (method A): retention time 9.15 minutes FAB MS: m / z 617 (M ⁺ + H) ¹ H NMR (300 MHz, CDCl ₃ ): free base: d
7.72 (s, 1H), 7.34 (br d, 1H),
7.15-7.25 (m, 4H), 6.98 (s, 1
H), 4.35 (m, 1H), 2.90 (s, 3H),
1.00 (s, 3H), 0.96 (s, 3H)

Example 65

[Chemical 110] The product of Example A in CHCl ₃ (100 ml) (1.10 g,
To a stirred solution of 2.74 mmol) at 0 ° C DIEA (0.7
5 ml, 4.3 mmol) and benzyl chloroformate (0.51 g, 3.0 mmol) were added. Solution at 0 ℃
At room temperature for 1 hour and then at ambient temperature for 14 hours.
The reaction mixture was concentrated under reduced pressure, and the residue was mixed with 10: 1 MeOH-NH ₄
It was dissolved in a 25 ml solution of OH. The mixture was concentrated under reduced pressure, the residue was dissolved in CHCl ₃ (100 ml) and 5% aqueous HCl (2 × 5).
0 ml) and aqueous NaHCO ₃ (100 ml). The organic phase was dried (MgSO ₄₎ filtered and the solvent was removed under reduced pressure. The residue was purified by pressure silica gel column chromatography using 1: 4 EtOAc-hexane as eluent.
Benzyl urethane was obtained as a white foam. TLC: Rf 0.40 (1: 3 EtOAc: Hexane) HPLC (Method A): Retention time 12.25 min FAB MS: m / z 537 (M ⁺ + H) Benzyl urethane (1.25 g, in DMF (20 ml).
To a stirred solution of 2.33 mmol) at 0 ° C. was added iodomethane (0.435 ml, 7.00 mmol) and sodium hydride (0.140 mg of a 60% dispersion in mineral oil, 3.50 mmol). The solution was stirred at 0 ° C. for 1 hour and then at ambient temperature for 18 hours. The reaction mixture was added to HOAc (1 m
l) and the solvent was removed under reduced pressure. The residue is EtOAc
Dissolve in (100 ml) and wash with aqueous NaHCO ₃ (2 × 50 ml). The organic phase was dried (MgSO ₄ ) filtered and the solvent removed under reduced pressure. The residue was purified by pressure silica gel column chromatography using 1: 5 EtOAc-hexane as eluent. N-methylbenzylurethane was obtained as a white foam. TLC: Rf 0.30 (1: 4 EtOAc: Hexane) HPLC (Method A): retention time 12.71 min FAB MS: m / z 551 (M ⁺ + H) 96: 4 N- in MeOH-HCO ₂ H (25 ml). To a solution of methylbenzylurethane (1.00 g, 1.82 mmol) in argon purge (stirred) was added palladium black (0.37 g). Reaction mixture at ambient temperature 16
Stir for hours. The catalyst was removed by filtration through Celite and the filtrate solvent was removed under reduced pressure. Residue as eluent 9
Purified by pressurized silica gel column chromatography using 5: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH. N-
The methyl endo-amine product was obtained as a white foam. TLC: Rf 0.35 (92: 8: 0.8 CHCl ₃ : Me
OH: NH ₄ OH) HPLC (Method A): Retention time 7.88 min FAB MS: m / z 417 (M ⁺ + H) in CHCl ₃ (50 ml) N-methylendo-amine (0.
650 g, 1.56 mmol) to a stirred solution of Na-Bo
Acid fluoride of c-L-methionine sulfone (510 mg,
1.80 mmol) and DIEA (0.35 ml, 2.0 mmol) were added. The mixture is stirred at ambient temperature for 48 hours,
Then 10% aqueous citric acid (2 x 30 ml), water (30
ml) and aqueous NaHCO ₃ (2 × 30 ml). The organic phase was dried (MgSO ₄₎ filtered and the solvent was removed under reduced pressure.
Dissolve the residue in CH ₂ Cl ₂ (10 ml) and add TFA (6 m) to the solution.
l) was added. The mixture was stirred at ambient temperature for 1.5 hours. The solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using a water-acetonitrile gradient containing 0.1% TFA. The TFA salt of the target compound was obtained as a lyophilized powder. _{Analysis: (C 29 H 45 N 3} O 5 S 2) · 0.4TFA · 0.5EtOAc Calculated: C, 57.04; H, 7.44 ; N, 6.28 Found: C, 57.04 ; H, 7.55; N, 6.28 TLC: Rf0.18 (95: 5: 0.5 CHCl 3: Me
OH: NH ₄ OH) HPLC (method A): retention time 9.80 minutes FAB MS: m / z 580 (M ⁺ + H) ¹ H NMR (300 MHz, CDCl ₃ ): d 7.15-
7.25 (m, 4H), 5.20 (m, 2H), 3.1
7 (s, 3H), 2.92 (s, 3H), 1.06
(S, 3H), 0.96 (s, 3H)

Example 66 Endo- (1S) -1 'in ethanol (20 ml)
(((2-amino-7,7-dimethylbicyclo [2.
2.1] -Hept-1-yl) -methyl) -sulfonyl) spiro (1H-indan-1,4′-piperidine (94 mg, 0.17 mmol) into a stirred solution of N- (3-
Bromopropyl) -phthalimide (69 mg, 0.255
Mmol), then diisopropylethylamine (0.
044 ml, 0.255 mmol) was added. The temperature was then warmed to 50 ° C. After about 18 hours the solution was cooled and then concentrated under reduced pressure. The residue was dissolved in methylene chloride (150 ml), washed with 1M HCl (2 × 150 ml) then dried over sodium sulfate and concentrated. Purification by flash chromatography (5% methanol in methylene chloride) as a white solid (45 mg, 40 mg)
%) Was obtained. Analysis: (C ₃₉ H ₅₀ N ₄ O ₆ S) ・ 0.10H ₂ O ・ 0.15CH ₂ C
l ₂ Calculated: C, 65.54; H, 7.10; N, 7.81 Found: C, 65.52; H, 7.09; N, 7.71 HPLC (Vydac C18 column). ; 0.1%
Gradient of 95/5 / 100 H20 / CH ₃ CN containing TFA, 15 min gradient, flow rate = 1.5 ml / min) Rt = 13.81 min, Purity = 100% ¹ H NMR: Consistent with structure FAB MS : m / z = 703 (M + + H)

In addition to the compounds specifically listed above, the compounds of the present invention are further illustrated in the following table. These compounds were synthesized by the synthetic routes and methods described in the reaction schemes and examples above, variations of which are well known to those skilled in the art and do not require unnecessary experimentation. All variants listed in the table below relate to the general formula:

[Chemical 111]

[0130]

[Chemical 112]

[Chemical 113]

[Chemical 114]

[Chemical 115]

[Chemical formula 116]

[Chemical 117]

[Chemical 118]

[Chemical formula 119]

[Chemical 120]

[Chemical 121]

[Chemical formula 122]

[Chemical 123]

[Chemical formula 124]

[Chemical 125]

[Chemical formula 126]

[0131]

[Chemical 127]

[Chemical 128]

[Chemical formula 129]

[Chemical 130]

[Chemical 131]

[Chemical 132]

Radioligand Binding Assay [ ³ H] OT to Uterine Oxytocin (OT) Receptor
([Tyrosyl, 3,5 ^[3 H] OT: 30-60Ci
/ Mmol; New England Nuclea, (Nuclear
) Boston, MA) High affinity binding assay using purified membrane preparations of uterus obtained from diethylstilbestrol dipropionate (DES) -treated (0.3 mg / kg, ip; 18-24) rats. ^It is based on ^* . For competition studies, assay buffer (50 mM Tris-HCl, 5 mM MgCl 2
1 nM [ ³ H] O in ₂ and 0.1% BSA, pH 7.4)
Performed under equilibrium with T (60 min, 22 ° C.). Non-specific binding (10% of total binding) 1 mM unlabeled O
The binding reaction was determined using T and the cell harvester (Model 7019, Scatron, Ink, Sterling (Skat
Ron, Inc. Sterling), VA) and terminated by filtration through a glass fiber filter. Male rats liver bound to crude membrane preparation (AVP-V ₁ sites) or kidney medulla (AVP-V ₂ sites) ^[3 H] vasopressin (AVP) ([phenylalanyl--3,4,5 ³ H]
AVP; 80-90 Ci / mmol; New England Nuclea) was measured by Butlen et al.
The method of ^** was performed. The competition assay was performed using assay buffer (100 mM Tris-HCl, 5 mM MgCl ₂ , 0.1%).
1 nM [ ³ H] in BSA, 50 mM phenylmethylsulfonyl fluoride and 50 mg / ml bactracin, pH 8.0)
It was carried out under equilibrium (30 minutes, 30 ° C.) using AVP (liver) or 2 nM [ ³ H] AVP (kidney). Non-specific binding (5-10% of total binding) was measured using 10 mM unlabeled AVP and the binding reaction was terminated by the above filtration for the [ ³ H] OT binding assay. Saturation binding assay ([ ³ H] OT (uterine), 0.7 nM; [ ³ H] A
VP (liver), 0.4 nM; ^[3 H] (kidney), 1.4 N
Using the Kd value obtained from M), the IC ₅₀ value (Ki = IC
It was obtained for each compound from 3-6 different measurements of _{50/1 + c / Kd)} ***.

While the present invention describes and describes certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions may be made herein without departing from the spirit and scope of the invention. Will recognize that it can be done. For example, as explained above, effective doses other than the preferred doses are applicable as an important modification to the responsiveness of the mammal being treated for the prevention of preterm delivery, and Other indications of the compounds of the invention shown in are applicable. Similarly observed specific pharmacological responses may vary depending on the particular active compound chosen, regardless of the drug carrier, the dosage form and the mode of administration used. Such anticipated variations or differences in results are intended in accordance with the purposes and practices of the invention. Accordingly, the invention is to be limited only by the scope of the following claims, which are to be broadly construed, where appropriate.
* Fuchis, A-R; Fuchis, F; Sorofu, MS, 19
1985 (Fuchs, AR: Fuchs, F; Soloff, MS. 198
5 ) J. Clin. Endocrinol. Metab. 60: 37 ** Butren, D; Giron, G; Ragerison, R .; M. Jard, S; Sawyer, W, H, Manning, M, 19
1978 (Butlen, D; Guillon, G; Rajerison, RM; J
ard, S; Sawyer, WH; Manning, M. 1978 ) Mol
Pharmacol 14: 1006. *** Cheng, Y-
C; Prusov, W.A. H. 1973 (Cheng, YC; Pr
usoff, WH; 1973) Biochem Pharmacol 22:
3099.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location C07D 401/12 207 209 211 213 223 233 237 257 405/12 221 409/12 221 413/12 221 417 / 12 221 417/14 209 C07F 9/576 9155-4H C07K 5/02 8318-4H (72) Inventor Ben E. Evans United States, 19446 Pennsylvania, Lancedale, Perkiomen Avenue 501 (72) Inventor Roger Em. Fredinger USA, 19446 Pennsylvania, Lancedale, Newport Lane 744 (72) Inventor Kevin Gilbert USA, 19503 Pennsylvania, Barry, Elm Street 665 (72) Inventor Doug W. A. Hobbes United States, 19446 Pennsylvania, Lancedale, Garfield Avenue 843 (72) Inventor George Ef. Randell United States, 19442 Pennsylvania, Bluebell, Hover Road 817 (72) Inventor Douglas J .. Petit Bourne USA, 18914 Pennsylvania, Chalfont, Hickory Lane 69 (72) Inventor Kenneth E. Liter United States, 18054 Pennsylvania, Green Lane, Old Woods Road 1955

Claims (15)

[Claims] 1. A compound having the following structural formula: And a pharmaceutically acceptable salt thereof, wherein X is C═O CH ₂ PO ₂ H O PO ₂ H—OY (Y is C _1-10 alkyl) S SO SO ₂ Or SO ₂ NH; m is an integer of 1 to 3; n is an integer of 0 to 2; p is an integer of 0 to 2; q is an integer of 0 to 1; r is 0 Is an integer of 5 to 5; R ¹ and R ² are each independently hydrogen halogen hydroxy C _1-10 alkyl C _1-10 alkoxy or trifluoromethyl; R ³ is hydrogen halogen hydroxy or oxo; ^{When 3} is oxo, the 2,3 bond is saturated; R ⁴ is hydrogen phenyl or C _1-15 alkyl; R ⁵ and R ⁶ are each independently hydrogen C _1-10 alkyl or C _{1 -10} hydroxyalkyl; further R ⁵ and R ^{6 taken} together form an oxo-fused phenyl or an unsubstituted or substituted C _3-6 cycloalkyl (wherein the substituents are hydroxy C _1-10 alkyl C _{1 -10} hydroxyalkyl C _1-10 alkoxy Further C _1-10 alkoxyalkyl alkoxyalkoxyalkyl); R ^7, R ⁸ and R ⁹ are each independently hydrogen unsubstituted or substituted C _1-10 alkyl (the substituent in the case cyano (C is 2 to 10 ) Hydroxy carboxy C _1-10 alkoxy C _1-10 alkoxycarbonyl or an unsubstituted or substituted 5-membered heterocycle having one heteroatom (wherein said heteroatom is N; said substituent is oxo amino C _1-10 alkylamino) C _1-10 carboxyalkyl an alkylcarbonylamino C _1-10 dicarboxylate alkylamino or C _1-10 di alkoxycarbonylalkyl amino)) C _1-10 dialkyl C _7-10 alkoxy C _1-10 alkoxycarbonyl C _{1 -10} Alkoxycarbonylalkylaminocarbonyl Fused phenyl cyano C _2-10 Cyanoalkyl phosphate C _1-10 Alkyl-Substituted Phosphonate Sulfate C _1-10 Alkyl-Substituted Sulfonate Halogen-Substituted C _1-10 Alkyl-Substituted Sulfonate (R ¹⁰ is hydrogen C _1-10 alkylsulfonyl C _1-10 alkarylsulfonyl C _1-10 aralkylsulfonyl C _1-10 alkoxyarylsulfonyl aminosulfonyl C _1-10 alkylaminosulfonyl C _1-10 dialkylaminosulfonyl unsubstituted or Substituted C _3-15 cycloalkylalkyl, bicycloalkyl or tricycloalkyl (substituent is oxo) or unsubstituted or substituted C _3-15 cycloalkylalkyl, bicycloalkyl or tricycloalkyl (substituent is oxo, oxime or R ¹¹ is hydrogen C _1-10 alkyl C _1-10 carboxyalkyl or C _1-10 alkoxycarbonylalkyl); (R ¹¹ is as defined above; R ¹² is hydrogen amino C _1-10 alkylamino unsubstituted or substituted C _1-10 alkyl (the above-mentioned substituents are unsubstituted or substituted C _4-8 cycloalkyl (substituents are hydroxy. Or carboxy) C _10-15 bi and tricycloalkyl halogen hydroxy carboxy oxo oxime C _1-10 alkylthio C _1-10 alkylsulfinyl C _1-10 alkylsulfonyl C _1-10 alkoxycarbonyl 1, 2, 3 or 4 Unsubstituted or substituted 4, 5, 6 or 7 membered heterocycle having a heteroatom or moiety (heteroatoms or moieties are N, S, SO, SO ₂ or O; substituents are C _1-10 alkyl C _{1- 10} aralkyl C _1-10 aralkoxy C _1-10 alkaryl amino C _1-10 alkylamino C _1-10 dialkylamino oxo oxime condensed phenyl C _1-10 alkoxy Cycarbonyl C _1-10 alkyl carbonate C _1-10 alkyl ureido C _1-10 alkyl carbamate or unsubstituted or substituted 5, 6 or 7 membered heterocycle having 1, 2, 3 or 4 heteroatoms (where the heteroatom is N , O
Or S; the substituent is oxo or fused phenyl). ) Unsubstituted or substituted phenyl (the above-mentioned substituents are halogen hydroxy carboxy C _1-10 alkyl C _1-10 carboxyalkyl C _1-10 alkoxy sulphate or 5, 6 or 7 member having 1, 2, 3 or 4 heteroatoms Heterocycle (where the heteroatom is N, O or S)
Amino aminocarbonyl C _1-10 dialkylaminocarbonyl C _1-10 alkylamino C _1-10 dialkylamino C _1-10 alkyl carbamate C _1-10 alkyl carbonate C _1-10 alkylureido C _1-10 aralkyl carbamate Substituted or substituted aryloxy (substituent is amino,
C _1-10 alkyl or C _1-10 aminoalkyl) C _1-10 aralkyloxy unsubstituted or substituted C _1-10 alkaryloxy (substituent is C _1-10 alkyl carbamate) N, N—C _1-10 alkyl-C _1-10 carboxyalkyl or N, N, N-C _1-10 dialkyl-C _1-10 alkoxycarbonylalkyl) unsubstituted or substituted C _3-8 cycloalkyl (substituent is C
_1-10 alkyl or carboxy) N, N-C _1-10 dialkyl unsubstituted or substituted C _7-15 bicycloalkyl or tricycloalkyl (substituent is carboxy) C _1-10 alkoxy unsubstituted or substituted phenyl (The above substituents are amino halogen C _1-10 alkyl C _1-10 alkoxy nitro phenylcarbonyl or an unsubstituted or substituted 5-, 6- or 7-membered heterocycle having 1, 2, 3 or 4 heterocycle atoms (where the heteroatom is Is O, N or S; the substituent is oxo) is) or unsubstituted or substituted 4, 5, 6, 7 or 8 membered mono- or bicyclohetero having 1, 2, 3 or 4 heteroatoms or moieties. Ring (heteroatoms or moieties are N, O, S,
SO or SO ₂ ; the substituent is oxo hydroxy carboxy amino C _1-10 carboxyalkyl C _1-10 alkyl C _1-10 alkoxy C _1-10 aralkoxy C _1-10 alkaryloxy C _1-10 alkoxycarbonyl C _{1 -10} alkoxycarbonylamino C _1-10 alkoxycarbonylalkyl C _1-10 aralkoxycarbonyl or substituted or unsubstituted aryl (substituent is C _1-5 alkyl, carboxy or halogen). And further R ⁷ and R ⁸ together are a 5, 6 or 7 membered heterocycle having 2, 3 or 4 heteroatoms (where the heteroatoms are N, O or S)-(CH ₂ ) _r -CO -NH-R ¹³ (R ¹³ is C _1-10 alkyl C _1-10 aminoalkyl C _1-10 alkoxycarbonylalkyl C _1-10 carboxyalkyl or has 1 or 2 heteroatoms 8 Membered bicycloheterocycle (where the heteroatom is N)-(CH ₂ ) _r NH-CO-NH-R ¹⁴ (R ¹⁴ is hydrogen-substituted or unsubstituted C _1-10 alkyl, C _7-15 bi or Tricycloalkyl (wherein the above substituent is carboxy C _1-10 alkoxycarbonyl aminocarbonyl or C _1-10 mono- or dialkylaminocarbonyl) substituted or unsubstituted phenyl (wherein the above substituent is hydroxy carboxy halogen C _1-10 alkyl or C _1-10 carboxyalkyl) or a substituted or unsubstituted 5, 6 or 7 membered heterocycle having 1 or 2 heteroatoms or moieties (wherein the heteroatoms or moieties are N, O, S, SO or SO ₂ ; substituent to form a a a) oxo carboxy amino C _1-10 carboxyalkyl C _1-10 alkyl or C _1-10 alkoxycarbonylamino) That]. 2. A compound having the following structural formula: And pharmaceutically acceptable salts thereof [In the above formula: X is a _{C = O CH 2 PO 2 O} P-OY (Y is a C _1-10 alkyl) S SO or SO _2; m is 1 to 3 N is an integer of 0 to 2; p is an integer of 0 to 1; q is an integer of 0 to ¹ ; r is an integer of 0 to 5; R ¹ and R ² Are each independently hydrogen halogen or C _1-10 alkyl; R ³ is hydrogen halogen hydroxy or oxo; provided that when R ³ is oxo, the 2,3 bond is saturated; R ⁴ is hydrogen Or phenyl; R ⁵ and R ⁶ are each independently hydrogen or C _1-10 alkyl; and R ⁵ and R ⁶ together are oxo fused phenyl or unsubstituted or substituted C _1-10 cycloalkyl (The above substituents are hydroxy C _1-10 hydroxyalkyl or C _1-10 alkoxyl R ⁷ , R ⁸ and R ⁹ are each independently hydrogen-unsubstituted or substituted C _1-10 alkyl (the above-mentioned substituents are cyano (when C is 2-10) hydroxy carboxy C) _1-10 alkoxy C _1-10 alkoxycarbonyl or an unsubstituted or substituted 5-membered heterocycle having 1 heteroatom (wherein the heteroatom is N; the substituent is oxo amino C _1-10 alkylamino C _1-10 Carboxyalkylcarbonylamino is C _1-10 dicarboxyalkylamino or C _1-10 dialkoxycarbonylalkylamino) C _1-10 dialkyl C _7-10 alkoxy C _1-10 alkoxycarbonyl C _1-10 alkoxycarbonyl alkylaminocarbonyl fused phenyl phosphates C _1-10 alkyl-substituted phosphonate sulphate C _1-10 A Kill substituted sulfonate halogen-substituted C _1-10 alkyl substituted sulfonate embedded image (R ¹⁰ is hydrogen C _1-10 alkylcarbonyl halogen sulfonyl C _1-10 alkylsulfonyl C _1-10 alkaryl sulfonyl C _1-10 alkoxycarbonyl arylsulfonylamino aminosulfonyl dialkylaminosulfonyl unsubstituted or substituted C _3-15 cycloalkylalkyl (Substituent is oxo) or sulfonyl substituted with unsubstituted or substituted C _3-15 cycloalkylalkyl (substituent is oxo); R ¹¹ is hydrogen C _1-10 alkyl C _1-10 carboxy Alkyl or C _1-10 alkoxycarbonylalkyl) (R ¹¹ is as defined above; R ¹² is hydrogen amino C _1-10 alkylamino unsubstituted or substituted C _1-10 alkyl (the above-mentioned substituents are unsubstituted or substituted C _5-6 cycloalkyl (substituents are hydroxy. C _10-15 tricycloalkyl halogen hydroxy carboxy oxo oxo C _1-10 alkylthio C _1-10 alkoxycarbonyl unsubstituted or substituted 5-, 6- or 7-membered heterocycle having 1, 2, 3 or 4 heteroatoms ( Heteroatoms are N, S
Or O; the substituent is C _1-10 alkyl C _1-10 aralkyl C _1-10 aralkoxy amino oxo fused phenyl C _1-10 alkoxycarbonyl C _1-10 alkyl carbamate or unsubstituted or substituted having 1 heteroatom A 5-membered heterocycle (where the heteroatom is N; the substituent is oxo or fused phenyl). ) Unsubstituted or substituted phenyl (the above-mentioned substituents are hydroxy carboxy C _1-10 alkyl C _1-10 carboxyalkyl C _1-10 alkoxy sulphate or a 5- or 6-membered heterocycle having 1 or 2 heteroatoms (where the heteroatom is N Or S)) amino alkylamino dialkylamino C _1-10 alkyl carbamate C _1-10 aralkyl carbamate unsubstituted or substituted aryloxy (substituent is amino,
C _1-10 alkyl or C _1-10 aminoalkyl) C _1-10 aralkyloxy unsubstituted or substituted C _1-10 alkaryloxy (substituent is C _1-10 alkyl carbamate) N, N—C _1-10 alkyl-C _1-10 carboxyalkyl or N, N, N-C _1-10 dialkyl-C _1-10 alkoxycarbonylalkyl) unsubstituted or substituted C _3-8 cycloalkyl (substituent is C
_1-10 alkyl or carboxy) N, N-C _1-10 dialkyl unsubstituted or substituted C ₇ bicycloalkyl (substituent is carboxy) C _1-10 alkoxy unsubstituted or substituted phenyl (the above substituents are amino Halogen C _1-10 alkyl C _1-10 alkoxy nitro phenylcarbonyl or an unsubstituted or substituted 5-membered heterocycle having one heterocyclic atom (heteroatom is O; substituent is oxo) Unsubstituted or substituted 4, 5, 6, 7 or 8 membered mono- or bicycloheterocycle having 1 or 2 heteroatoms (heteroatoms are N, O or S; substituents are oxo hydroxy carboxy C _1-10 carboxy alkyl C _1-10 alkyl C _1-10 alkoxy C _1-10 aralkoxy C _1-10 alkoxycarbonyl C _1-10 alkoxycarbonyl alkyl Or C _1-10 is aralkoxycarbonyl carbonyl)); and 5-membered heterocyclic ring (hetero atom R ⁷ and R ⁸ having two hetero atoms together are N, or O), or _{- (CH 2) r -CO-} NH-R 13 (R 13 is C _1-10 alkyl C _1-10 aminoalkyl, or C _1-10 alkoxycarbonylalkyl) forms a]. 3. A pharmaceutical composition comprising a pharmacologically effective amount of the compound according to claim 1, which antagonizes the binding of oxytocin at its receptor site, and a pharmaceutically acceptable carrier. 4. A method for preventing preterm birth in mammals (excluding humans), which comprises the step of administering to said mammal a pharmacologically effective amount of the compound according to claim 1. 5. A method of treating dysmenorrhea in a mammal (excluding humans), which comprises the step of administering to said mammal a pharmacologically effective amount of the compound according to claim 1. 6. A method of terminating labor in a mammal (excluding humans) prior to Caesarean delivery, comprising the step of administering to said mammal a pharmacologically effective amount of the compound of claim 1. Method. 7. A method of antagonizing the binding of mammalian (except human) oxytocin at its receptor site, which comprises administering to said mammal a pharmacologically effective amount of the compound of claim 1. A method consisting of steps. 8. A compound of the following formula: 9. A pharmaceutical composition comprising a pharmacologically effective amount of the compound according to claim 8 which antagonizes the binding of oxytocin at its receptor site, and a pharmacologically acceptable carrier. 10. A method for preventing preterm birth in a mammal (excluding humans), which comprises the step of administering to said mammal a pharmacologically effective amount of the compound according to claim 8. 11. A method of treating dysmenorrhea in a mammal (excluding humans), which comprises the step of administering to said mammal a pharmacologically effective amount of a compound according to claim 8. 12. A method of terminating labor in a mammal (excluding humans) prior to Caesarean delivery, comprising the step of administering to said mammal a pharmacologically effective amount of the compound of claim 8. Method. 13. A method of antagonizing the binding of oxytocin at its receptor site in mammals (excluding humans), which comprises administering to said mammal a pharmacologically effective amount of the compound according to claim 8. A method consisting of steps to do. 14. A compound of the formula: embedded image And a pharmaceutically acceptable salt thereof. 15. A compound of the formula: embedded image And a pharmaceutically acceptable salt thereof.